Benzimidazol-2-amines as midh1 inhibitors

ABSTRACT

The present invention relates to benzimidazol-2-amines of general formula (I), in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 and R12 are as defined herein, to methods of preparing said compounds, to intermediate compounds useful for preparing said compounds, to pharmaceutical compositions and combinations comprising said compounds and to the use of said compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular of neoplasms, as a sole agent or in combination with other active ingredients.

The present invention relates to benzimidazol-2-amine compounds ofgeneral formula (I) as described and defined herein, to methods ofpreparing said compounds, to intermediate compounds useful for preparingsaid compounds, to pharmaceutical compositions and combinationscomprising said compounds and to the use of said compounds formanufacturing a pharmaceutical composition for the treatment orprophylaxis of a disease, in particular of neoplasms, as a sole agent orin combination with other active ingredients.

BACKGROUND OF THE INVENTION

The present invention relates to chemical compounds that inhibit mutatedisocitratdehydrogenase 1 (mIDH1 R132H), to methods of preparing saidcompounds, to pharmaceutical compositions and combinations comprisingsaid compounds, to the use of said compounds for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease, as well as to intermediate compounds useful in the preparationof said compounds.

Isocitrate dehydrogenases (IDH) are key enzymes in cellular metabolism,converting isocitrate to alpha-ketoglutarate and belong to 2 subgroups,defined by the utilization of different electron receptor. Two of them,isocitrate dehydrogenase 1 and 2 use NADP(+) as electron receptor. IDH1is located in the cytoplasm and peroxisomes and IDH2 in the mitochondriaas an integral part of the TCA cycle, e.g in the following reaction:

Isocitrate+NADP⁺→alpha-ketoglutarate+CO₂+NADPH+H⁺

Both enzymes act as homodimers.

In a variety of tumor entities, including glioma, acute myeloid leukemia(AML), chondrosarcoma, cholangiocarcinoma, melanoma, prostate cancer,angioimmunoblastic T-cell lymphoma and others, IDH1 or IDH2 are mutatedat a distinct amino acid position (Balss J. Acta Neuropathol. 2008December; 116(6):597-602, Mardis E R, N Engl J Med. 2009 Sep. 10;361(11):1058-66, Amary M F, J Pathol. 2011 July; 224(3):334-43, Borger DR, Oncologist. 2012; 17(1):72-9, Shibata T, Am J Pathol. 2011 March;178(3):1395-402, Ghiam A F, Oncogene. 2012 Aug. 16; 31(33):3826, CairnsR A, Blood. 2012 Feb. 23; 119(8):1901-3). This mutation is alwaysheterozygous and mutual exclusive. Most of these point mutations havebeen found at key positions in the catalytic domain of the enzyme(responsible 2-oxoglutarate coordination), e.g. IDH1R100, IDH1R132,IDH1G97 and IDH2R140, IDH2R172 (Dang L., Nature, 2009 Dec. 10;462(7274):739-44). In glioma, more than 70% of all non-primaryglioblastoma are IDH1 mutated and in 92.7% of the IDH1 mutated tumorsthe arginine was replaced by a histidine (IDH1R132H). (Hartmann C, ActaNeuropathol. 2009 October; 118(4):469-74).

The replacement of the wildtype amino acid at those catalytic residuesleads to a neomorphic activity of the enzyme, convertingalpha-ketoglutarate to R-2-hydroxyglutarate (2-HG). 2-HG is metabolicwaste, but also an oncometabolite and it is believed to contribute totumorgenesis (Dang L., Nature, 2009 Dec. 10; 462(7274):739-44) 2-HG isonly produced in very low levels in normal cells, but cells harboringthe IDH mutations produce high levels of 2-HG. High amounts of 2-HG havealso been found in tumors with the IDH mutation. IDH mutations have alsobeen described in patient with other disorders with high 2-HG levels,e.g. in a rare neurometabolic disorder characterized bysupraphysiological levels of 2-HG (2-HG aciduria) (Kranendijk M,Science. 2010 Oct. 15; 330(6002):336).

Hence, the inhibition of IDH mutations and its neomorphic activity is apotential therapeutic treatment option for tumors and other IDH mutationrelated disorders.

WO02/092575A1 relates to benzimidazole compounds as inhibitors ofmembrane fusion associated events, such as transfusion.

WO03/007945A1 and WO02/04425A2 relates inter alia to benzimidazolecompounds as inhibitors of RNA dependent RNA polymerases.

WO2009/059214A1 relates to Aβ-binding benzimidazole derivatives.

WO2008/153701A1 relates to benzimidazole compounds as inhibitors of KSPkinesin activity.

WO2005/121132A1 relates to fused heterocyclic compounds having anti-HCVeffect.

EP0385850A2 discloses benzimidazole and azabenzimidazole derivatives forthe treatment of cardiovascular diseases and duodenal ulcers.

WO00/32578 A1 discloses benzimidazole compounds as vitronectin receptorantagonists.

WO02004/085425A1 discloses inter alia benzimidazole compounds havingVEGFR/KDR inhibitory activity.

EP1810677A1 discloses benzimidazole compounds as GPR40 receptor functionregulators.

EP1069124A1 discloses 2-benzimidazolylamine compounds as ORL1-receptoragonists.

WO02010/034796A1 discloses benzimidazole compounds as inhibitors ofenzymes belonging to the membrane-associated proteins in the eicosanoidand gluthathione metabolism family.

WO2009/116074A2 discloses substituted benzimidazoles as cannabinoidmodulators.

WO03/074515A1 discloses benzimidazole derivatives as TIE-2 and/orVEGFR-2 inhibitors.

WO02005/044793A2 discloses inter alia benzimidazole compounds as CRFreceptor antagonists.

WO2006/099379A2 discloses benzazole derivatives as beta-secretaseinhibitors.

WO2010/100249A1 discloses inter alia benzimidazole compounds asinhibitors of the microsomal prostaglandin E2 synthase-1.

WO2010/151441A1 discloses benzamide derivatives which influence theviability of SKOV3 and A2780 cells.

However, the state of the art described above does not describe thespecific substituted benzimidazole compounds of general formula (I) ofthe present invention as defined herein, or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, or a mixture ofsame, as described and defined herein, and as hereinafter referred to as“compounds of the present invention”, or their pharmacological activity.

It has now been found, and this constitutes the basis of the presentinvention, that said compounds of the present invention have surprisingand advantageous properties.

In particular, said compounds of the present invention have been foundto effectively inhibit mutated isocitratdehydrogenase 1 (mIDH1 R132H)and may therefore be used for the treatment or prophylaxis of diseasesof uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses or diseases which are accompanied withuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, for example, haematological tumours, solid tumours, and/ormetastases thereof, e.g. leukaemias and myelodysplastic syndrome,malignant lymphomas including angioimmunoblastic T-cell lymphomas, headand neck tumours including brain tumours and brain metastases (e.g.anaplastic astrocytoma, diffuse astrocytoma, glioblastoma,oligodendroglioma, secondary glioblastoma multiforme), tumours of thethorax including non-small cell and small cell lung tumours,gastrointestinal tumours including cholangiocarcinoma, endocrinetumours, mammary and other gynaecological tumours, urological tumoursincluding renal, bladder and prostate tumours, skin tumours, andsarcomas including chondrosarcomas, and/or metastases thereof.

DESCRIPTION OF THE INVENTION

In accordance with a first aspect, the present invention coverscompounds of general formula (I):

in which

-   R¹ represents a halogen atom or group selected from:    -   C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-alkoxy,        C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,        (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, cyano, nitro, (C₁-C₆-alkyl)-S—,        (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,        (C₁-C₆-haloalkyl)-S—, (C₁-C₆-haloalkyl)-S(═O)—,        (C₁-C₆-haloalkyl)-S(═O)₂—, —C(═O)O R¹³, —C(═O)N(R¹⁴)R¹⁵,        —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, aryl-O—, aryl-(C₁-C₃-alkyl)-,        heteroaryl-O—, and heteroaryl-(C₁-C₃-alkyl)-;    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom or a halogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from:    -   C₁-C₆-alkyl, C₁-C₆-alkoxy, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl,        C₁-C₆-haloalkoxy, cyano, nitro, (C₁-C₆-alkyl)-S—,        (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,        (C₁-C₆-haloalkyl)-S—, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹, R¹⁰, and R¹¹    -   are independently of each other selected from: hydrogen and        C₁-C₃-alkyl;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl,        H₂N—(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, aryl, heteroaryl,        aryl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-;    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)NH₂;-   or-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,    HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl,    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, aryl, heteroaryl, and 4- to    6-membered heterocycloalkyl;    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

The terms as mentioned in the present text have preferably the followingmeanings:

The term “halogen atom”, “halo-” or “Hal-” is to be understood asmeaning a fluorine, chlorine, bromine or iodine atom.

The term “C₁-C₆-alkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group having 1, 2,3, 4, 5, or 6 carbon atoms, e.g. a methyl, ethyl, propyl, butyl, pentyl,hexyl, iso-propyl, iso-butyl, sec-butyl, tert-butyl, iso-pentyl,2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl,neo-pentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl,2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl,3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl,2,3-dimethylbutyl, 1,3-dimethylbutyl, or 1,2-dimethylbutyl group, or anisomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkyl”), e.g. a methyl, ethyl, propyl, butyl, iso-propyl,iso-butyl, sec-butyl, tert-butyl group, more particularly 1, 2 or 3carbon atoms (“C₁-C₃-alkyl”), e.g. a methyl, ethyl, n-propyl- oriso-propyl group.

The term “C₁-C₆-haloalkyl” is to be understood as preferably meaning alinear or branched, saturated, monovalent hydrocarbon group in which theterm “C₁-C₆-alkyl” is defined supra, and in which one or more hydrogenatom is replaced by a halogen atom, in identically or differently, i.e.one halogen atom being independent from another. Particularly, saidhalogen atom is F. Said C₁-C₆-haloalkyl group is, for example, —CF₃,—CHF₂, —CH₂F, —CF₂CF₃, CH₂CH₂F, CH₂CHF₂, CH₂CF₃, or CH₂CH₂CF₃.

The term “C₁-C₆-alkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent, group of formula—O—(C₁-C₆-alkyl), in which the term “C₁-C₆-alkyl” is defined supra, e.g.a methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy,tert-butoxy, sec-butoxy, pentoxy, iso-pentoxy, or n-hexoxy group, or anisomer thereof. Particularly, said group has 1, 2, 3 or 4 carbon atoms(“C₁-C₄-alkoxy”), e.g. a methoxy, ethoxy, propoxy, butoxy, iso-propoxy,iso-butoxy, sec-butoxy, tert-butoxy group, more particularly 1, 2 or 3carbon atoms (“C₁-C₃-alkoxy”), e.g. a methoxy, ethoxy, n-propoxy- oriso-propoxy- group.

The term “(C₁-C₆-alkoxy)-(C₁-C₆-alkyl)” is to be understood aspreferably meaning a linear or branched, saturated, monovalentC₁-C₆-alkyl group, as defined supra, in which one or more of thehydrogen atoms is replaced, in identically or differently, by aC₁-C₆-alkoxy group, as defined supra, e.g. methoxyalkyl, ethoxyalkyl,propyloxyalkyl, iso-propoxyalkyl, butoxyalkyl, iso-butoxyalkyl,tert-butoxyalkyl, sec-butoxyalkyl, pentyloxyalkyl, iso-pentyloxyalkyl,hexyloxyalkyl group, or an isomer thereof.

The term “C₁-C₆-haloalkoxy” is to be understood as preferably meaning alinear or branched, saturated, monovalent C₁-C₆-alkoxy group, as definedsupra, in which one or more of the hydrogen atoms is replaced, inidentically or differently, by a halogen atom. Particularly, saidhalogen atom is F. Said C₁-C₆-haloalkoxy group is, for example, —OCF₃,—OCHF₂, —OCH₂F, —OCF₂CF₃, or —OCH₂CF₃.

The term “C₂-C₆-alkenyl” is to be understood as preferably meaning alinear or branched, monovalent hydrocarbon group, which contains one ormore double bonds, and which has 2, 3, 4, 5 or 6 carbon atoms,particularly 2 or 3 carbon atoms (“C₂-C₃-alkenyl”), it being understoodthat in the case in which said alkenyl group contains more than onedouble bond, then said double bonds may be isolated from, or conjugatedwith, each other. Said alkenyl group is, for example, a vinyl, allyl,(E)-2-methylvinyl, (Z)-2-methylvinyl, homoallyl, (E)-but-2-enyl,(Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl,(E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl,(E)-pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl,(Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl,(Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl,2-methylprop-2-enyl, 1-methylprop-2-enyl, 2-methylprop-1-enyl,(E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl,2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl,(E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl,(Z)-1-methylbut-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl,(E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl,(Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl,1-propylvinyl, 1-isopropylvinyl, 4-methylpent-4-enyl,3-methylpent-4-enyl, 2-methylpent-4-enyl, 1-methylpent-4-enyl,4-methylpent-3-enyl, (E)-3-methylpent-3-enyl, (Z)-3-methylpent-3-enyl,(E)-2-methylpent-3-enyl, (Z)-2-methylpent-3-enyl,(E)-1-methylpent-3-enyl, (Z)-1-methylpent-3-enyl,(E)-4-methylpent-2-enyl, (Z)-4-methylpent-2-enyl,(E)-3-methylpent-2-enyl, (Z)-3-methylpent-2-enyl,(E)-2-methylpent-2-enyl, (Z)-2-methylpent-2-enyl,(E)-1-methylpent-2-enyl, (Z)-1-methylpent-2-enyl,(E)-4-methylpent-1-enyl, (Z)-4-methylpent-1-enyl,(E)-3-methylpent-1-enyl, (Z)-3-methylpent-1-enyl,(E)-2-methylpent-1-enyl, (Z)-2-methylpent-1-enyl,(E)-1-methylpent-1-enyl, (Z)-1-methylpent-1-enyl, 3-ethylbut-3-enyl,2-ethylbut-3-enyl, 1-ethylbut-3-enyl, (E)-3-ethylbut-2-enyl,(Z)-3-ethylbut-2-enyl, (E)-2-ethylbut-2-enyl, (Z)-2-ethylbut-2-enyl,(E)-1-ethylbut-2-enyl, (Z)-1-ethylbut-2-enyl, (E)-3-ethylbut-1-enyl,(Z)-3-ethylbut-1-enyl, 2-ethylbut-1-enyl, (E)-1-ethylbut-1-enyl,(Z)-1-ethylbut-1-enyl, 2-propylprop-2-enyl, 1-propylprop-2-enyl,2-isopropylprop-2-enyl, 1-isopropylprop-2-enyl, (E)-2-propylprop-1-enyl,(Z)-2-propylprop-1-enyl, (E)-1-propylprop-1-enyl,(Z)-1-propylprop-1-enyl, (E)-2-isopropylprop-1-enyl,(Z)-2-isopropylprop-1-enyl, (E)-1-isopropylprop-1-enyl,(Z)-1-isopropylprop-1-enyl, (E)-3,3-dimethylprop-1-enyl,(Z)-3,3-dimethylprop-1-enyl, 1-(1,1-dimethylethyl)ethenyl,buta-1,3-dienyl, penta-1,4-dienyl, hexa-1,5-dienyl, or methylhexadienylgroup. Particularly, said group is vinyl or allyl.

The term “C₃-C₆-cycloalkyl” is to be understood as meaning a saturated,monovalent, monocyclic hydrocarbon ring which contains 3, 4, 5 or 6carbon atoms. Said C₃-C₆-cycloalkyl group is for example, a monocyclichydrocarbon ring, e.g. a cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl ring.

The term “C₃-C₆-cycloalkyloxy” is to be understood as meaning asaturated, monovalent, monocyclic hydrocarbon group of formula—O—(C₃-C₆-cycloalkyl), in which the term “C₃-C₆-cycloalkyl” is definedsupra, e.g. a. a cyclopropyloxy, cyclobutyloxy, cyclopentyloxy orcyclohexyloxy group.

The term “4- to 6-membered heterocycloalkyl”, is to be understood asmeaning a saturated, monovalent, monocyclic hydrocarbon ring whichcontains 3, 4 or 5, carbon atoms, and one or two heteroatom-containinggroups selected from: O, S, S(═O), S(═O)₂, and NR^(a), in which R^(a)represents a hydrogen atom, or a C₁-C₆-alkyl- group, and wherein onecarbon atom is optionally replaced by C(═O); it being possible for saidheterocycloalkyl group to be attached to the rest of the molecule viaany one of the carbon atoms or, if present, a nitrogen atom.

Particularly, without being limited thereto, said heterocycloalkyl canbe a 4-membered ring, such as azetidinyl or oxetanyl, or a 5-memberedring, such as tetrahydrofuranyl, dioxolinyl, pyrrolidinyl,imidazolidinyl or pyrazolidinyl, or a 6-membered ring, such astetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinylor piperazinyl.

The term “aryl” is to be understood as preferably meaning a monovalent,aromatic or partially aromatic, mono- or bicyclic hydrocarbon ringhaving 6, 7, 8, 9 or 10 carbon atoms (a “C₆-C₁₀-aryl” group),particularly having 6 carbon atoms (a “C₆-aryl” group), e.g. a phenylgroup; or a biphenyl group, or having 9 carbon atoms (a “C₆-aryl”group), e.g. an indanyl or indenyl group, or having 10 carbon atoms (a“C₁₀-aryl” group), e.g. a tetralinyl, dihydronaphthyl, or naphthylgroup. Preferably, the aryl group is a phenyl group.

The term “heteroaryl” is understood as preferably meaning a monovalent,monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7,8, 9, 10, 11, 12, 13 or 14 ring atoms (a “5- to 14-membered heteroaryl”group), particularly 5 or 6 or 9 or 10 atoms, and which contains atleast one heteroatom which may be identical or different, saidheteroatom being such as oxygen, nitrogen or sulfur, and in addition ineach case can be benzocondensed. Particularly, heteroaryl is selectedfrom: thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,thiadiazolyl, thia-4H-pyrazolyl, benzofuranyl, benzothienyl,benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzotriazolyl, indazolyl,indolyl, isoindolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,triazinyl, quinolinyl, quinazolinyl, isoquinolinyl, azocinyl,indolizinyl, purinyl, cinnolinyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthpyridinyl, pteridinyl, carbazolyl, acridinyl,phenazinyl, phenothiazinyl, phenoxazinyl, xanthenyl, and oxepinyl.

In general, and unless otherwise mentioned, the heteroaryl groupincludes all the possible isomeric forms thereof, e.g. the positionalisomers thereof. Thus, for some illustrative non-restricting example,the term pyridinyl includes pyridin-2-yl, pyridin-3-yl, andpyridin-4-yl; or the term thienyl includes thien-2-yl, and thien-3-yl.

The term “C₁-C₆”, as used throughout this text, e.g. in the context ofthe definition of “C₁-C₆-alkyl”, “C₁-C₆-haloalkyl”, “C₁-C₆-alkoxy”, or“C₁-C₆-haloalkoxy” is to be understood as meaning an alkyl group havinga finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5, or 6carbon atoms. It is to be understood further that said term “C₁-C₆” isto be interpreted as any sub-range comprised therein, e.g. C₁-C₆, C₂-C₅,C₃-C₄, C₁-C₂, C₁-C₃, C₁-C₄, C₁-C₅; particularly C₁-C₂, C₁-C₃, C₁-C₄,C₁-C₅, C₁-C₆; more particularly C₁-C₄; in the case of “C₁-C₆-haloalkyl”or “C₁-C₆-haloalkoxy” even more particularly C₁-C₂.

Similarly, as used herein, the term “C₂-C₆”, as used throughout thistext, e.g. in the context of the definitions of “C₂-C₆-alkyl”, and“C₂-C₆-alkenyl” is to be understood as meaning an alkenyl group or analkynyl group having a finite number of carbon atoms of 2 to 6, i.e. 2,3, 4, 5, or 6 carbon atoms. It is to be understood further that saidterm “C₂-C₆” is to be interpreted as any sub-range comprised therein,e.g. C₂-C₆, C₃-C₅, C₃-C₄, C₂-C₃, C₂-C₄, C₂-C₅; particularly C₂-C₃.

Further, as used herein, the term “C₃-C₆”, as used throughout this text,e.g. in the context of the definition of “C₃-C₆-cycloalkyl”, is to beunderstood as meaning a cycloalkyl group having a finite number ofcarbon atoms of 3 to 6, i.e. 3, 4, 5 or 6 carbon atoms. It is to beunderstood further that said term “C₃-C₆” is to be interpreted as anysub-range comprised therein, e.g. C₃-C₆, C₄-C₅, C₃-C₅, C₃-C₄, C₄-C₆,C₅-C₆; particularly C₃-C₆.

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties.

Ring system substituent means a substituent attached to an aromatic ornonaromatic ring system which, for example, replaces an availablehydrogen on the ring system.

As used herein, the term “one or more”, e.g. in the definition of thesubstituents of the compounds of the general formulae of the presentinvention, is understood as meaning “one, two, three, four or five,particularly one, two, three or four, more particularly one, two orthree, even more particularly one or two”.

The invention also includes all suitable isotopic variations of acompound of the invention. An isotopic variation of a compound of theinvention is defined as one in which at least one atom is replaced by anatom having the same atomic number but an atomic mass different from theatomic mass usually or predominantly found in nature. Examples ofisotopes that can be incorporated into a compound of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulphur, fluorine, chlorine, bromine and iodine, such as ²H (deuterium),³H (tritium), ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³²P, ³³P, ³³S, ³⁴S, ³⁵S,³⁶S, ¹⁸F, ³⁶Cl, ⁸²Br, ¹²³I, ¹²⁴I, ¹²⁹I and ¹³¹I, respectively. Certainisotopic variations of a compound of the invention, for example, thosein which one or more radioactive isotopes such as ³H or ¹⁴C areincorporated, are useful in drug and/or substrate tissue distributionstudies. Tritiated and carbon-14, i.e., ¹⁴C, isotopes are particularlypreferred for their ease of preparation and detectability. Further,substitution with isotopes such as deuterium may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample, increased in vivo half-life or reduced dosage requirements andhence is preferred in some circumstances. Isotopic variations of acompound of the invention can generally be prepared by conventionalprocedures known by a person skilled in the art such as by theillustrative methods or by the preparations described in the exampleshereafter using appropriate isotopic variations of suitable reagents.

Where the plural form of the word compounds, salts, polymorphs,hydrates, solvates and the like, is used herein, this is taken to meanalso a single compound, salt, polymorph, isomer, hydrate, solvate or thelike.

By “stable compound” or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The compounds of this invention optionally contain one or moreasymmetric centre, depending upon the location and nature of the varioussubstituents desired. Asymmetric carbon atoms is present in the (R) or(S) configuration, resulting in racemic mixtures in the case of a singleasymmetric centre, and diastereomeric mixtures in the case of multipleasymmetric centres. In certain instances, asymmetry may also be presentdue to restricted rotation about a given bond, for example, the centralbond adjoining two substituted aromatic rings of the specifiedcompounds.

The compounds of the present invention optionally contain sulphur atomswhich are asymmetric, such as an asymmetric sulfoxide, of structure:

for example,

in which * indicates atoms to which the rest of the molecule can bebound.

Substituents on a ring may also be present in either cis or trans form.It is intended that all such configurations (including enantiomers anddiastereomers), are included within the scope of the present invention.

Preferred compounds are those which produce the more desirablebiological activity. Separated, pure or partially purified isomers andstereoisomers or racemic or diastereomeric mixtures of the compounds ofthis invention are also included within the scope of the presentinvention. The purification and the separation of such materials can beaccomplished by standard techniques known in the art.

The optical isomers can be obtained by resolution of the racemicmixtures according to conventional processes, for example, by theformation of diastereoisomeric salts using an optically active acid orbase or formation of covalent diastereomers. Examples of appropriateacids are tartaric, diacetyltartaric, ditoluoyltartaric andcamphorsulfonic acid. Mixtures of diastereoisomers can be separated intotheir individual diastereomers on the basis of their physical and/orchemical differences by methods known in the art, for example, bychromatography or fractional crystallisation. The optically active basesor acids are then liberated from the separated diastereomeric salts. Adifferent process for separation of optical isomers involves the use ofchiral chromatography (e.g., chiral HPLC columns), with or withoutconventional derivatisation, optimally chosen to maximise the separationof the enantiomers. Suitable chiral HPLC columns are manufactured byDaicel, e.g., Chiracel OD and Chiracel OJ among many others, allroutinely selectable. Enzymatic separations, with or withoutderivatisation, are also useful. The optically active compounds of thisinvention can likewise be obtained by chiral syntheses utilizingoptically active starting materials.

In order to limit different types of isomers from each other referenceis made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

The present invention includes all possible stereoisomers of thecompounds of the present invention as single stereoisomers, or as anymixture of said stereoisomers, e.g. R- or S-isomers, or E- or Z-isomers,in any ratio. Isolation of a single stereoisomer, e.g. a singleenantiomer or a single diastereomer, of a compound of the presentinvention is achieved by any suitable state of the art method, such aschromatography, especially chiral chromatography, for example.

Further, the compounds of the present invention may exist as tautomers.For example, any compound of the present invention which contains apyrazole moiety as a heteroaryl group for example can exist as a 1Htautomer, or a 2H tautomer, or even a mixture in any amount of the twotautomers, namely:

The present invention includes all possible tautomers of the compoundsof the present invention as single tautomers, or as any mixture of saidtautomers, in any ratio.

Further, the compounds of the present invention can exist as N-oxides,which are defined in that at least one nitrogen of the compounds of thepresent invention is oxidised. The present invention includes all suchpossible N-oxides.

The present invention also relates to useful forms of the compounds asdisclosed herein, such as metabolites, hydrates, solvates, prodrugs,salts, in particular pharmaceutically acceptable salts, andco-precipitates.

The compounds of the present invention can exist as a hydrate, or as asolvate, wherein the compounds of the present invention contain polarsolvents, in particular water, methanol or ethanol for example asstructural element of the crystal lattice of the compounds. The amountof polar solvents, in particular water, may exist in a stoichiometric ornon-stoichiometric ratio. In the case of stoichiometric solvates, e.g. ahydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta- etc.solvates or hydrates, respectively, are possible. The present inventionincludes all such hydrates or solvates.

Further, the compounds of the present invention can exist in free form,e.g. as a free base, or as a free acid, or as a zwitterion, or can existin the form of a salt. Said salt may be any salt, either an organic orinorganic addition salt, particularly any pharmaceutically acceptableorganic or inorganic addition salt, customarily used in pharmacy.

The term “pharmaceutically acceptable salt” refers to a relativelynon-toxic, inorganic or organic acid addition salt of a compound of thepresent invention. For example, see S. M. Berge, et al. “PharmaceuticalSalts,” J. Pharm. Sci. 1977, 66, 1-19.

A suitable pharmaceutically acceptable salt of the compounds of thepresent invention may be, for example, an acid-addition salt of acompound of the present invention bearing a nitrogen atom, in a chain orin a ring, for example, which is sufficiently basic, such as anacid-addition salt with an inorganic acid, such as hydrochloric,hydrobromic, hydroiodic, sulfuric, bisulfuric, phosphoric, or nitricacid, for example, or with an organic acid, such as formic, acetic,acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic,heptanoic, undecanoic, lauric, benzoic, salicylic,2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic,cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nicotinic,pamoic, pectinic, persulfuric, 3-phenylpropionic, picric, pivalic,2-hydroxyethanesulfonate, itaconic, sulfamic, trifluoromethanesulfonic,dodecylsulfuric, ethansulfonic, benzenesulfonic, para-toluenesulfonic,methansulfonic, 2-naphthalenesulfonic, naphthalinedisulfonic,camphorsulfonic acid, citric, tartaric, stearic, lactic, oxalic,malonic, succinic, malic, adipic, alginic, maleic, fumaric, D-gluconic,mandelic, ascorbic, glucoheptanoic, glycerophosphoric, aspartic,sulfosalicylic, hemisulfuric, or thiocyanic acid, for example.

Further, another suitably pharmaceutically acceptable salt of a compoundof the present invention which is sufficiently acidic, is an alkalimetal salt, for example a sodium or potassium salt, an alkaline earthmetal salt, for example a calcium or magnesium salt, an ammonium salt ora salt with an organic base which affords a physiologically acceptablecation, for example a salt with N-methyl-glucamine, dimethyl-glucamine,ethyl-glucamine, lysine, dicyclohexylamine, 1,6-hexadiamine,ethanolamine, glucosamine, sarcosine, serinol,tris-hydroxy-methyl-aminomethane, aminopropandiol, sovak-base,1-amino-2,3,4-butantriol. Additionally, basic nitrogen containing groupsmay be quaternised with such agents as lower alkyl halides such asmethyl, ethyl, propyl, and butyl chlorides, bromides and iodides;dialkyl sulfates like dimethyl, diethyl, and dibutyl sulfate; and diamylsulfates, long chain halides such as decyl, lauryl, myristyl andstrearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others.

Those skilled in the art will further recognise that acid addition saltsof the claimed compounds may be prepared by reaction of the compoundswith the appropriate inorganic or organic acid via any of a number ofknown methods. Alternatively, alkali and alkaline earth metal salts ofacidic compounds of the invention are prepared by reacting the compoundsof the invention with the appropriate base via a variety of knownmethods.

The present invention includes all possible salts of the compounds ofthe present invention as single salts, or as any mixture of said salts,in any ratio.

In the present text, in particular in the Experimental Section, for thesynthesis of intermediates and of examples of the present invention,when a compound is mentioned as a salt form with the corresponding baseor acid, the exact stoichiometric composition of said salt form, asobtained by the respective preparation and/or purification process, is,in most cases, unknown.

Unless specified otherwise, suffixes to chemical names or structuralformulae such as “hydrochloride”, “trifluoroacetate”, “sodium salt”, or“x HCl”, “x CF₃COOH”, “x Na⁺”, for example, are to be understood as nota stoichiometric specification, but solely as a salt form.

This applies analogously to cases in which synthesis intermediates orexample compounds or salts thereof have been obtained, by thepreparation and/or purification processes described, as solvates, suchas hydrates with (if defined) unknown stoichiometric composition.

As used herein, the term “in vivo hydrolysable ester” is understood asmeaning an in vivo hydrolysable ester of a compound of the presentinvention containing a carboxy or hydroxy group, for example, apharmaceutically acceptable ester which is hydrolysed in the human oranimal body to produce the parent acid or alcohol. Suitablepharmaceutically acceptable esters for carboxy include for examplealkyl, cycloalkyl and optionally substituted phenylalkyl, in particularbenzyl esters, C₁-C₆ alkoxymethyl esters, e.g. methoxymethyl, C₁-C₆alkanoyloxymethyl esters, e.g. pivaloyloxymethyl, phthalidyl esters,C₃-C₈ cycloalkoxy-carbonyloxy-C₁-C₆ alkyl esters, e.g.1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters, e.g.5-methyl-1,3-dioxolen-2-onylmethyl; and C₁-C₆-alkoxycarbonyloxyethylesters, e.g. 1-methoxycarbonyloxyethyl, and may be formed at any carboxygroup in the compounds of this invention.

An in vivo hydrolysable ester of a compound of the present inventioncontaining a hydroxy group includes inorganic esters such as phosphateesters and [alpha]-acyloxyalkyl ethers and related compounds which as aresult of the in vivo hydrolysis of the ester breakdown to give theparent hydroxy group. Examples of [alpha]-acyloxyalkyl ethers includeacetoxymethoxy and 2,2-dimethylpropionyloxymethoxy. A selection of invivo hydrolysable ester forming groups for hydroxy include alkanoyl,benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl,alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. The present invention covers allsuch esters.

Furthermore, the present invention includes all possible crystallineforms, or polymorphs, of the compounds of the present invention, eitheras single polymorph, or as a mixture of more than one polymorph, in anyratio.

The present invention covers compounds of general formula (I), supra, inwhich R¹ represents a halogen atom or group selected from: C₁-C₆-alkyl,C₃-C₆-cycloalkyl, C₁-C₆-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, cyano, nitro,(C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,(C₁-C₆-haloalkyl)-S—, (C₁-C₆-haloalkyl)-S(═O)—,(C₁-C₆-haloalkyl)-S(═O)₂—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵,—N(R¹⁴)C(═O)R¹⁶, aryl-O—, aryl-(C₁-C₃-alkyl)-, heteroaryl-O—, andheteroaryl-(C₁-C₃-alkyl)-;

wherein aryl and heteroaryl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹ represents a group selectedfrom: C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,cyano, nitro, (C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, and aryl-O—;

wherein aryl and heteroaryl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-alkoxy,C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,(C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, cyano, nitro, (C₁-C₆-alkyl)-S—,(C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—,(C₁-C₆-haloalkyl)-S(═O)—, (C₁-C₆-haloalkyl)-S(═O)₂—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, aryl-O—,aryl-(C₁-C₃-alkyl)-, heteroaryl-O—, and heteroaryl-(C₁-C₃-alkyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₆-alkyl, C₁-C₆-alkoxy, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, cyano, nitro, (C₁-C₆-alkyl)-S(═O)₂—,(C₁-C₆-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵,—N(R¹⁴)C(═O)R¹⁶, and aryl-O—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy,C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy,(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, cyano, nitro, (C₁-C₃-alkyl)-S—,(C₁-C₃-alkyl)-S(═O)—, (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—,(C₁-C₃-haloalkyl)-S(═O)—, (C₁-C₃-haloalkyl)-S(═O)₂—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, phenyl-O—,phenyl-(C₁-C₃-alkyl)-, pyridinyl-O—, and pyridinyl-(C₁-C₃-alkyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, cyano, nitro, (C₁-C₃-alkyl)-S(═O)₂—,(C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵,—N(R¹⁴)C(═O)R¹⁶.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, cyano, nitro, (C₁-C₃-alkyl)-S(═O)₂—,(C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵,—N(R¹⁴)C(═O)R¹⁶, phenyl-O—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, cyano, nitro, (C₁-C₃-alkyl)-S(═O)₂—,(C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, cyano, (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—,—N(R¹⁴)R¹⁵, phenyl-O—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—,—N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₂-C₃-alkyl, C₂-C₃-alkoxy, C₁-haloalkyl, C₁-haloalkoxy,cyano, nitro, (C₁-alkyl)-S(═O)₂—, (C₁-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, phenyl-O—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: C₂-C₃-alkyl, C₂-C₃-alkoxy, C₁-haloalkyl, C₁-haloalkoxy,cyano, (C₁-alkyl)-S(═O)₂—, (C₁-haloalkyl)-S—, —N(R¹⁴)R¹⁵, phenyl-O—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: ethyl-, ethoxy-, phenoxy-, —CN, —CF₃, —O—CF₃, —S—CF₃,iso-propyl-, iso-propoxy-, —O—CHF₂, —S(═O)₂CH₃, —N(CH₃)₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: ethyl-, ethoxy-, —CF₃, —O—CF₃, iso-propyl-, iso-propoxy-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: —CF₃, iso-propoxy-, —O—CF₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents —O—CF₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: ethyl-, ethoxy-, iso-propyl-, iso-propoxy-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: —C(H)(CH₃)₂, —CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃,—O—C(H)(CH₃)₂, —CN.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: —CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃, —O—C(H)(CH₃)₂, —CN,—C(H)(CH₃)₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹ represents a groupselected from: —CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃, —O—C(H)(CH₃)₂, —CN,—C(H)(CH₃)₂, —C(═O)OH.

The present invention covers compounds of general formula (I), supra, inwhich R⁴ represents a hydrogen atom or a halogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁴ represents ahydrogen atom or a fluorine atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁴ represents ahydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁴ represents afluorine atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—CH₂—CH₂—CH₂—, R¹³OC(═O)—CH₂—CH₂—,R¹³OC(═O)—CH₂—, R¹⁴(R¹⁵)NC(═O)—CH₂—CH₂—, R¹⁴(R¹⁵)NC(═O)—CH₂—,R¹³OC(═O)—CH₂—O—, R¹⁴(R¹⁵)NC(═O)—CH₂—O—,

wherein * indicates the point of attachment of said groups with the restof the molecule.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—CH₂—CH₂—, R¹³OC(═O)—CH₂—,R¹⁴(R¹⁵)NC(═O)—CH₂—CH₂—, R¹⁴(R¹⁵)NC(═O)—CH₂—, R¹³OC(═O)—CH₂—O—,R¹⁴(R¹⁵)NC(═O)—CH₂—O—,

wherein * indicates the point of attachment of said groups with the restof the molecule.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkoxy)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—(C₁-C₃-alkyl)- andR¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—(C₁-C₂-alkyl)- andR¹⁴(R¹⁵)NC(═O)—(C₁-C₂-alkyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ representsR¹³OC(═O)—CH₂—CH₂—CH₂—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ representsR¹³OC(═O)—CH₂—CH₂—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ representsR¹³OC(═O)—CH₂—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: —CH₂—CH₂—C(═O)—O—CH₃, —CH₂—CH₂—C(═O)—OH.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents—CH₂—CH₂—C(═O)—O—CH₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents—CH₂—CH₂—C(═O)—OH.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: —CH₂—C(═O)—O—CH₃, —CH₂—C(═O)—OH.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents—CH₂—C(═O)—O—CH₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents—CH₂—C(═O)—OH.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ representsR¹⁴(R¹⁵)NC(═O)—CH₂—CH₂—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: —CH₂—CH₂—C(═O)—NH₂, —CH₂—CH₂—C(═O)—N(CH3)₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—(C₂-C₄-alkenyl)- andR¹⁴(R¹⁵)NC(═O)—(C₂-C₄-alkenyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—(C₂-alkenyl)- and R¹⁴(R¹⁵)NC(═O)—(C₂-alkenyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—(C₂-alkenyl)- and R¹⁴(R¹⁵)NC(═O)—(C₂-alkenyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents

wherein * indicates the point of attachment of said group with the restof the molecule.

In particular, the present invention relates to compounds of generalformula (I), supra, in which R⁵ represents a group selected from:—C(H)═C(H)—C(═O)—OH, —C(H)═C(H)—C(═O)—O—CH₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents

wherein * indicates the point of attachment of said group with the restof the molecule.

In particular, the present invention relates to compounds of generalformula (I), supra, in which R⁵ represents a group selected from:—CH₂—CH₂—C(═O)—NH₂, —CH₂—CH₂—C(═O)—N(CH₃)₂.

In particular, the present invention relates to compounds of generalformula (I), supra, in which R⁵ represents a group selected from:—CH₂—C(═O)—NH₂, —CH₂—C(═O)—N(CH₃)₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—(C₁-C₃-alkoxy)- andR¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkoxy)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: R¹³OC(═O)—CH₂—O— and R¹⁴(R¹⁵)NC(═O)—CH₂—O—.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: —O—CH₂—C(═O)—O—C(CH₃)₃, —O—CH₂—C(═O)—OH,—O—CH₂—CH₂—CH₂—C(═O)—OH, —O—CH₂—C(═O)—N(H)-cyclopropyl,—O—CH₂—C(═O)—N(H)—CH₂—C(═O)—O—CH₃, —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—O—CH₃,—O—CH₂—C(═O)—N(H)—CH₂—C(═O)—OH, —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—OH.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: —O—CH₂—C(═O)OH, —O—CH₂—C(═O)OC(CH₃)₃, —CH═CH—C(═O)OH,—CH═CH—C(═O)—O—CH₃, —CH₂—CH₂—C(═O)OH, —CH═CH—C(═O)—NH₂,—CH═CH—C(═O)—N(CH₃)₂, —CH₂—CH₂—C(═O)—NH₂, —CH₂—CH₂—C(═O)—N(CH₃)₂,—O—CH₂—C(═O)OH, —O—CH₂—CH₂—CH₂—C(═O)OH, —O—CH₂—C(═O)—NH—CH₂—C(═O)OH,—O—CH₂—C(═O)—NH—CH₂—C(═O)—O—CH₃, —O—CH₂—C(═O)—NH-(cyclopropyl).

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁵ represents a groupselected from: —O—CH₂—C(═O)—O—C(CH₃)₃, —O—CH₂—C(═O)—OH,—O—CH₂—CH₂—CH₂—C(═O)—OH, —O—CH₂—C(═O)—N(H)-cyclopropyl,—O—CH₂—C(═O)—N(H)—CH₂—C(═O)—O—CH₃, —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—O—CH₃,—O—CH₂—C(═O)—N(H)—CH₂—C(═O)—OH, —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—OH,—CH₂—CH₂—C(═O)—O—CH₃, —CH₂—CH₂—C(═O)—OH, —CH₂—CH₂—C(═O)—NH₂,—CH₂—CH₂—C(═O)—N(CH₃)₂, —C(H)═C(H)—C(═O)—OH, —C(H)═C(H)—C(═O)—O—CH₃,—C(H)═C(H)—C(═O)—NH₂, —C(H)═C(H)—C(═O)—N(CH₃)₂.

The present invention covers compounds of general formula (I), supra, inwhich R⁶ represents a hydrogen atom or a halogen atom or group selectedfrom: C₁-C₆-alkyl, C₁-C₆-alkoxy, C₃-C₆-cycloalkyl,(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl,C₁-C₆-haloalkoxy, cyano, nitro, (C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—,(C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—, —N(R¹⁴)R¹⁵, and—N(R¹⁴)C(═O)R¹⁶.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁶ represents a hydrogen atom or ahalogen atom or group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano,nitro, (C₁-C₃-alkyl)-S—, (C₁-C₃-alkyl)-S(═O)—, (C₁-C₃-alkyl)-S(═O)₂—,(C₁-C₃-haloalkyl)-S—, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents ahydrogen atom or a halogen atom or group selected from: C₁-C₃-alkyl,C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents H, —CH₃,—O—CH₃ or —CH₂—O—CH₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents H, F,—CH₃, —O—CH₃ or —CH₂—O—CH₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents ahydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents ahalogen atom, preferably a fluorine or chlorine atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents amethyl- group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents amethoxy- group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁶ represents—CH₂—O—CH₃.

The present invention covers compounds of general formula (I), supra, inwhich R⁸ represents a C₁-C₃-alkyl group.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁸ represents a C₁-C₂-alkyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents a methylgroup.

The present invention covers compounds of general formula (I), supra, inwhich R⁹, R¹⁰, and R¹¹ are independently of each other selected from:hydrogen and C₁-C₃-alkyl.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R⁹, R¹⁰, and R¹¹ are independentlyof each other selected from: hydrogen and methyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents a methylgroup, R⁹ represents a hydrogen atom or a methyl group, R¹⁰ represents amethyl group, and R¹¹ represents a methyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents a methylgroup, R⁹ represents a hydrogen atom, R¹⁰ represents a methyl group, andR¹¹ represents a methyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R⁸ represents a methylgroup, R⁹ represents a methyl group, R¹⁰ represents a methyl group, andR¹¹ represents a methyl group.

The present invention covers compounds of general formula (I), supra, inwhich R¹³ represents a hydrogen atom or a group selected from:C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and(C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹³ represents a hydrogen atom or agroup selected from: C₁-C₄-alkyl, HO—(C₂-C₃-alkyl)-, and(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹³ represents ahydrogen atom or a C₁-C₄-alkyl-group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹³ represents ahydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹³ represents aC₁-C₄-alkyl- group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹³ represents —H,—CH₃, or —C(CH₃)₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹³ represents —H.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹³ represents —CH₃.

The present invention covers compounds of general formula (I), supra, inwhich R¹⁴ and R¹⁵ are independently of each other selected from:hydrogen, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,(C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl, H₂N—(C₂-C₆-alkyl)-,(C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-,R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to 6-membered heterocycloalkyl, aryl,heteroaryl, aryl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-;

wherein aryl and heteroaryl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)NH₂;

or R¹⁴ and R¹⁵ together with the nitrogen atom to which they areattached form a 4-6-membered heterocycloalkyl; said 4-6-memberedheterocycloalkyl being optionally substituted with one substituentselected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy,halogen, and cyano; or said 4-6-membered heterocycloalkyl beingoptionally substituted with two halogen atoms.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹⁴ and R¹⁵ are independently ofeach other selected from: hydrogen, C₁-C₃-alkyl, C₃-C₆-cycloalkyl,HO—(C₂-C₃-alkyl)-, (C₁-C₃-alkoxy)-(C₂-C₃-alkyl)-, C₁-C₃-haloalkyl,H₂N—(C₂-C₃-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₃-alkyl)-,(C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, 4-6 memberedheterocycloalkyl, phenyl, pyridinyl, phenyl-(C₁-C₃-alkyl)-, andpyridinyl-(C₁-C₃-alkyl)-;

wherein phenyl and pyridinyl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)NH₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ areindependently of each other selected from: hydrogen, C₁-C₃-alkyl,C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-, (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-,R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to 6-membered heterocycloalkyl, phenyl,phenyl-(C₁-C₃-alkyl)-, and pyridinyl-(C₁-C₃-alkyl)-;

wherein phenyl and pyridinyl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)NH₂.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ areindependently of each other selected from: hydrogen, C₁-C₃-alkyl,C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-, (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-,R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to 6-membered heterocycloalkyl, phenyl,phenyl-(C₁-C₃-alkyl)-, and pyridinyl-(C₁-C₃-alkyl)-;

wherein phenyl and pyridinyl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, and—C(═O)OR¹³.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ areindependently of each other selected from: hydrogen, C₁-C₃-alkyl,C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, andphenyl;

wherein the phenyl group is optionally substituted with one or twosubstituents, which are independently of each other selected from:C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ areindependently of each other selected from: hydrogen, C₁-C₃-alkyl,C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, andphenyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ togetherwith the nitrogen atom to which they are attached form a 4-6-memberedheterocycloalkyl; said 4-6-membered heterocycloalkyl being optionallysubstituted with one substituent selected from: C₁-C₃-alkyl,C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen, and cyano; or said4-6-membered heterocycloalkyl being optionally substituted with twohalogen atoms.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ and R¹⁵ togetherwith the nitrogen atom to which they are attached form a 4-6-memberedheterocycloalkyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ represents ahydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁴ represents amethyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁵ represents ahydrogen atom or a group selected from: —CH₃, cyclopropyl,—CH₂—C(═O)—OH, —CH₂—C(═O)—O—CH₃, phenyl, and pyridinyl,

wherein phenyl and pyridinyl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: F, Cl, —CH₃, —CHF₂, —CF₃, —OCHF₂, —OCF₃, —C(═O)OCH₃.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁵ represents ahydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁵ represents amethyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁵ represents acyclopropyl group.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁵ represents a—CH₂—C(═O)—OH group or a —CH₂—C(═O)—O—CH₃ group.

The present invention covers compounds of general formula (I), supra, inwhich R¹⁶ represents a hydrogen atom or a group selected from:C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-,aryl, heteroaryl, and 4- to 6-membered heterocycloalkyl;

wherein aryl and heteroaryl groups are optionally substituted with oneor two substituents, which are independently of each other selectedfrom: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I), supra, in which R¹⁶ represents a hydrogen atom or agroup selected from: C₁-C₃-alkyl, HO—(C₁-C₃-alkyl)-, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,phenyl, heteroaryl, and 4- to 6-membered heterocycloalkyl; whereinphenyl and heteroaryl groups are optionally substituted with one or twosubstituents, which are independently of each other selected from:C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy,C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and—C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom or a group selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,phenyl, and 4- to 6-membered heterocycloalkyl; wherein the phenyl groupis optionally substituted with one or two substituents, which areindependently of each other selected from: C₁-C₃-alkyl,C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)N(R¹⁴)R¹⁵.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom or a group selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,HO—(C₃-C₆-cycloalkyl)-, C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,phenyl, and 4- to 6-membered heterocycloalkyl; wherein the phenyl groupis optionally substituted with one or two halogen atoms.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom or a group selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, and phenyl.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents ahydrogen atom.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which R¹⁶ represents a groupselected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, and(C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-.

It is to be understood that the present invention relates also to anycombination of the preferred embodiments described above.

Some examples of combinations are given hereinafter. However, theinvention is not limited to these combinations.

In a preferred embodiment, the present invention relates to compounds ofgeneral formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³,    —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom or a halogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl,        H₂N—(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, aryl, heteroaryl,        aryl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-,    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)NH₂;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,    HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl,    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, aryl, heteroaryl, and 4- to    6-membered heterocycloalkyl;    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I), supra, in which

-   R¹ represents a halogen atom or group selected from:    -   C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-alkoxy,        C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,        (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, cyano, nitro, (C₁-C₆-alkyl)-S—,        (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,        (C₁-C₆-haloalkyl)-S—, (C₁-C₆-haloalkyl)-S(═O)—,        (C₁-C₆-haloalkyl)-S(═O)₂—, —C(═O)OR¹³, —C(═O)N(R¹⁴)R¹⁵,        N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, aryl-O—, aryl-(C₁-C₃-alkyl)-,        heteroaryl-O—, and heteroaryl-(C₁-C₃-alkyl)-;    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₆-alkyl, C₁-C₆-alkoxy, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-,    C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl,    C₁-C₆-haloalkoxy, cyano, nitro, (C₁-C₆-alkyl)-S—,    (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—,    —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶;-   R⁷ represents a hydrogen atom;-   R⁸ represents a C₁-C₃-alkyl group;-   R⁹, R¹⁰, and R¹¹    -   are independently of each other selected from: hydrogen and        C₁-C₃-alkyl;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl,        H₂N—(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, aryl, heteroaryl,        aryl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-,    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)NH₂;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,    HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl,    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, aryl, heteroaryl, and 4- to    6-membered heterocycloalkyl;    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³,    —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-, and    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl,        H₂N—(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, aryl, heteroaryl,        aryl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-,    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)NH₂;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₆-alkyl, HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl,    HO—(C₃-C₆-cycloalkyl)-, C₁-C₆-haloalkyl,    (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, aryl, heteroaryl, and 4- to    6-membered heterocycloalkyl;    -   wherein aryl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₃-C₆-cycloalkyl,        C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and        —C(═O)N(R¹⁴)R¹⁵;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³,    —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom or a halogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₄-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₃-alkyl)-, and        pyridinyl-(C₁-C₃-alkyl)-;    -   wherein phenyl and pyridinyl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₃-C₆-cycloalkyl)-,    C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, phenyl, and 4- to    6-membered heterocycloalkyl;    -   wherein the phenyl group is optionally substituted with one or        two halogen atoms;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³,    —C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₄-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₃-alkyl)-, and        pyridinyl-(C₁-C₃-alkyl)-;    -   wherein phenyl and pyridinyl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₃-C₆-cycloalkyl)-,    C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, phenyl, and 4- to    6-membered heterocycloalkyl;    -   wherein the phenyl group is optionally substituted with one or        two halogen atoms;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, —N(R¹⁴)R¹⁵,    and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom or a halogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₄-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₃-alkyl)-, and        pyridinyl-(C₁-C₃-alkyl)-;    -   wherein phenyl and pyridinyl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;-   or-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₃-C₆-cycloalkyl)-,    C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, phenyl, and 4- to    6-membered heterocycloalkyl;    -   wherein the phenyl group is optionally substituted with one or        two halogen atoms;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, —N(R¹⁴)R¹⁵,    and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹³OC(═O)—(C₁-C₆-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —OCH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₄-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₃-alkyl)-, and        pyridinyl-(C₁-C₃-alkyl)-;    -   wherein phenyl and pyridinyl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;    -   said 4-6-membered heterocycloalkyl being optionally substituted        with one substituent selected from: C₁-C₃-alkyl,        C₁-C₃-haloalkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkoxy,        C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy, halogen,        and cyano;    -   or said 4-6-membered heterocycloalkyl being optionally        substituted with two halogen atoms;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₃-C₆-cycloalkyl)-,    C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, phenyl, and 4- to    6-membered heterocycloalkyl;    -   wherein the phenyl group is optionally substituted with one or        two halogen atoms;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, —N(R¹⁴)R¹⁵,    and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom or a halogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₄-alkenyl)-,        R¹³OC(═O)—(C₁-C₃-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₄-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₄-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₃-alkyl)-, and        pyridinyl-(C₁-C₃-alkyl)-;    -   wherein phenyl and pyridinyl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₃-C₆-cycloalkyl)-,    C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, phenyl, and 4- to    6-membered heterocycloalkyl;    -   wherein the phenyl group is optionally substituted with one or        two halogen atoms;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano, nitro,    (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³, —N(R¹⁴)R¹⁵,    and —N(R¹⁴)C(═O)R¹⁶;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₄-alkenyl)-,        R¹³OC(═O)—(C₁-C₃-alkoxy)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₂-C₄-alkenyl)-, R¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkoxy)-;-   R⁶ represents a hydrogen atom or a halogen atom or group selected    from: C₁-C₃-alkyl, C₁-C₃-alkoxy, and C₁-C₂-alkoxy-C₁-C₂-alkyl-;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃; or    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₄-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₃-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₃-alkyl)-, R¹³OC(═O)—(C₁-C₃-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₃-alkyl)-, and        pyridinyl-(C₁-C₃-alkyl)-;    -   wherein phenyl and pyridinyl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or

-   R¹⁴ and R¹⁵    -   together with the nitrogen atom to which they are attached form        a 4-6-membered heterocycloalkyl;-   R¹⁶ represents a hydrogen atom or a group selected from:    C₁-C₃-alkyl, C₃-C₆-cycloalkyl, HO—(C₃-C₆-cycloalkyl)-,    C₁-C₃-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, phenyl, and 4- to    6-membered heterocycloalkyl;    -   wherein the phenyl group is optionally substituted with one or        two halogen atoms;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, and —C(═O)OR¹³;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-;        R¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkoxy)-;-   R⁶ represents a hydrogen atom or a fluorine atom or group selected    from: C₁-C₃-alkyl, and C₁-C₃-alkoxy;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹ represent    -   —H, —H, —CH₃, —CH₃;    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₆-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₆-alkyl)-, and        heteroaryl-(C₁-C₆-alkyl)-,    -   wherein phenyl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a C₁-C₃-haloalkyl- group;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-;-   R⁶ represents a hydrogen atom;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₆-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₆-alkyl)-, and        heteroaryl-(C₁-C₆-alkyl)-,    -   wherein phenyl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from: C₁-C₃-alkyl, C₁-C₃-alkoxy,    C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, and —C(═O)OR¹³;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom or a fluorine atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-,        R¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkoxy)-;-   R⁶ represents a hydrogen atom or a fluorine atom or group selected    from: C₁-C₃-alkyl, and C₁-C₃-alkoxy;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —H, —H, —CH₃, —CH₃;    -   —CH₃, —H, —CH₃, —CH₃;    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₆-alkyl- group;-   R¹⁴ and R¹⁵    -   are independently of each other selected from: hydrogen,        C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,        (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-, R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to        6-membered heterocycloalkyl, phenyl, phenyl-(C₁-C₆-alkyl)-, and        heteroaryl-(C₁-C₆-alkyl)-,    -   wherein phenyl and heteroaryl groups are optionally substituted        with one or two substituents, which are independently of each        other selected from: C₁-C₃-alkyl, C₁-C₃-haloalkyl,        C₁-C₃-haloalkoxy, halogen, and —C(═O)OR¹³;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a C₁-C₃-haloalkyl- group;-   R² represents a hydrogen atom;-   R³ represents a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—(C₁-C₆-alkyl)-, R¹³OC(═O)—(C₂-C₆-alkenyl)-;-   R⁶ represents a hydrogen atom;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —CH₃, —H, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;-   R¹³ represents a hydrogen atom or a C₁-C₆-alkyl- group;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from:    -   —C(H)(CH₃)₂, —CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃, —O—C(H)(CH₃)₂,        —CN;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   R¹³OC(═O)—CH₂—CH₂—, R¹³OC(═O)—CH₂—, R¹⁴(R¹⁵)NC(═O)—CH₂—CH₂—,        R¹⁴(R¹⁵)NC(═O)—CH₂—, R¹³OC(═O)—CH₂—O—, R¹⁴(R¹⁵)N C(═O)—CH₂—O—,

-   -   wherein * indicates the point of attachment of said groups with        the rest of the molecule;

-   R⁶ represents a group selected from:    -   —H, —CH₃, —O—CH₃;

-   R⁷ represents a hydrogen atom;

-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;

-   R¹² represents a hydrogen atom;

-   R¹³ represents a hydrogen atom or a group selected from: —CH₃,    —C(CH₃)₃;

-   R¹⁴ represents a hydrogen atom or a methyl group;

-   R¹⁵ represents a hydrogen atom or a group selected from:    -   methyl, cyclopropyl, —CH₂—C(═O)—OH, —CH₂—C(═O)—O—CH₃;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from:    -   —C(H)(CH₃)₂, —CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃, —O—C(H)(CH₃)₂,        —CN;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   —O—CH₂—C(═O)—O—C(CH₃)₃, —O—CH₂—C(═O)—OH,        —O—CH₂—CH₂—CH₂—C(═O)—OH, —O—CH₂—C(═O)—N(H)-cyclopropyl,        —O—CH₂—C(═O)—N(H)—CH₂—C(═O)—O—CH₃,        —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—O—CH₃,        —O—CH₂—C(═O)—N(H)—CH₂—C(═O)—OH,        —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—OH, —CH₂—CH₂—C(═O)—O—CH₃,        —CH₂—CH₂—C(═O)—OH, —CH₂—C(═O)—O—CH₃, —CH₂—C(═O)—OH,        —CH₂—CH₂—C(═O)—NH₂, —CH₂—CH₂—C(═O)—N(CH₃)₂, —C(H)═C(H)—C(═O)—OH,        —C(H)═C(H)—C(═O)—O—CH₃, —C(H)═C(H)—C(═O)—NH₂,        —C(H)═C(H)—C(═O)—N(CH₃)₂;-   R⁶ represents a group selected from:    -   —H, —CH₃, —O—CH₃;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —CH₃, —H, —CH₃, —CH₃; or    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from:    -   —C(H)(CH₃)₂, —CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃, —O—C(H)(CH₃)₂,        —CN;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from:    -   —CH₂—CH₂—C(═O)—O—CH₃, —CH₂—CH₂—C(═O)—OH, —CH₂—C(═O)—O—CH₃,        —CH₂—C(═O)—OH;-   R⁶ represents a group selected from:    -   —H, —CH₃, —O—CH₃, —CH₂—O—CH₃;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —CH₃, —H, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

In another preferred embodiment, the present invention relates tocompounds of general formula (I):

in which:

-   R¹ represents a group selected from:    -   —C(H)(CH₃)₂, —CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃, —O—C(H)(CH₃)₂,        —CN;-   R² represents a hydrogen atom;-   R³ represents is a hydrogen atom;-   R⁴ represents a hydrogen atom;-   R⁵ represents a group selected from: —CH₂—CH₂—C(═O)—O—CH₃,    —CH₂—CH₂—C(═O)—OH, —CH₂—C(═O)—O—CH₃, —CH₂—C(═O)—OH;-   R⁶ represents a hydrogen atom or group selected from:    -   —CH₃, —O—CH₃, —CH₂—O—CH₃;-   R⁷ represents a hydrogen atom;-   R⁸, R⁹, R¹⁰, R¹¹ represent    -   —CH₃, —CH₃, —CH₃, —CH₃;-   R¹² represents a hydrogen atom;

or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of same.

It is to be understood that the present invention relates to anysub-combination within any embodiment or aspect of the present inventionof compounds of general formula (I), supra.

More particularly still, the present invention covers compounds ofgeneral formula (I) which are disclosed in the Example section of thistext, infra.

In accordance with another aspect, the present invention covers methodsof preparing compounds of the present invention, said methods comprisingthe steps as described in the Experimental Section herein.

In accordance with a further aspect, the present invention coversintermediate compounds which are useful for the preparation of thecompounds of general formula (I), supra.

Particularly, the inventions covers intermediate compounds of generalformula (II):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra; and intermediate compounds ofgeneral formula (IV):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra.

More particularly still, the present invention covers the intermediatecompounds which are disclosed in the Example section of this text,infra.

In accordance with a further aspect, the present invention covers theuse of the intermediate compounds of general formula (II):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra, for the preparation of a compoundof general formula (I) as defined supra.

In accordance with yet another aspect, the present invention covers theuse of the intermediate compounds of general formula (IV):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra, for the preparation of a compoundof general formula (I) as defined supra.

In accordance with a further aspect, the present invention relates tocompounds of general formula (I), as described supra, or a stereoisomer,a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof,particularly a pharmaceutically acceptable salt thereof, or a mixture ofsame, for use in the treatment or prophylaxis of a disease.

In accordance with a further aspect, the present invention relates to apharmaceutical composition comprising a compound of general formula (I),as described supra, or a stereoisomer, a tautomer, an N-oxide, ahydrate, a solvate, or a salt thereof, particularly a pharmaceuticallyacceptable salt thereof, or a mixture of same, and a pharmaceuticallyacceptable diluent or carrier.

Particularly, the pharmaceutical combination comprises:

-   -   one or more first active ingredients selected from a compound of        general formula (I) as described supra, and    -   one or more second active ingredients selected from        chemotherapeutic anti-cancer agents (see below).

In accordance with a further aspect, the present invention relates touse of a compound of general formula (I), as described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the prophylaxis or treatment of a disease.

In accordance with a further aspect, the present invention relates touse of a compound of general formula (I), as described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the preparation of a medicament for the prophylaxisor treatment of a disease.

The disease as mentioned before is in particular a disease ofuncontrolled cell growth, proliferation and/or survival, aninappropriate cellular immune response, or an inappropriate cellularinflammatory response, particularly in which the disease of uncontrolledcell growth, proliferation and/or survival, inappropriate cellularimmune response, or inappropriate cellular inflammatory response is ahaematological tumour, a solid tumour and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

EXPERIMENTAL SECTION

The following table 1 lists the abbreviations used in this paragraph andin the Examples section as far as they are not explained within the textbody. NMR peak forms are stated as they appear in the spectra, possiblehigher order effects have not been considered. Chemical names weregenerated using the ICS naming tool of ACD labs. In some cases generallyaccepted names of commercially available reagents were used in place ofICS naming tool generated names.

TABLE 1 Abbreviations Abbreviation Meaning br. broad signal in NMR br.s. broad singlet CDI di-1H-imidazol-1-ylmethanone conc. concentrated DCMdichloromethane DEA diethylamine DMF N,N-dimethylformamide d doublet dddoublet of doublets DMSO dimethyl sulfoxide EDCN-(3-dimethylaminopropyI)-N′-ethylcarbodiimide hydrochloride ESIelectrospray ionization EtOH ethanol h hour(s) HATU1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate HCl hydrochloric acid HCOOH formic acid HPLC,LC high performance liquid chromatography LiOH lithium hydroxide mmultiplet m_(c) centered multiplet min minute(s) MeCN acetonitrile MSmass spectroscopy MeOH methanol NaOH sodium hydroxide Na₂SO₄ sodiumsulfate NH₄Cl ammonium chloride NMP N-methyl-2-pyrrolidone NMR nuclearmagnetic resonance Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium PyBOP(benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphatequint quintet R_(t) retention time rt room temperature s singlet septseptet t triplet THF tetrahydrofurane UPLC ultra performance liquidchromatography

Other abbreviations have their meanings customary per se to the skilledperson. The various aspects of the invention described in thisapplication are illustrated by the following examples which are notmeant to limit the invention in any way.

Syntheses of Compounds (Overview)

The following schemes and general procedures illustrate generalsynthetic routes to the compounds of general formula (I) of theinvention and are not intended to be limiting. It is obvious to theperson skilled in the art that the order of transformations asexemplified in Schemes 1 to 3 can be modified in various ways. The orderof transformations exemplified in Schemes 1 to 3 is therefore notintended to be limiting. In addition, interconversion of substituents,for example of residues R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ can be achievedbefore and/or after the exemplified transformations. These modificationscan be such as the introduction of protecting groups, cleavage ofprotecting groups, reduction or oxidation of functional groups,halogenation, metallation, substitution or other reactions known to theperson skilled in the art. These transformations include those whichintroduce a functionality which allows for further interconversion ofsubstituents. Appropriate protecting groups and their introduction andcleavage are well-known to the person skilled in the art (see forexample T. W. Greene and P. G. M. Wuts, Protective Groups in OrganicSynthesis, 3rd edition, Wiley 1999).

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined supra, and X represents a halogen atom.

Suitably functionalized diamines of formula (II) may be reacted withthioisocyanates of general formula (III) in a suitable solvent such asfor example tetrahydrofurane and in the presence of a carbodiimide suchas for example diisopropylcarbodiimide or EDC at temperatures between 0°C. and the boiling point of the solvent, typically at 70° C.Thioisocyanates (III) are either commercially available, known compoundsor may be formed from known compounds by known methods by a personskilled in the art.

Diamines of general formula (II) in turn may be obtained fromnitroanilines of general formula 3 by reduction. For reduction, allprocesses that are known to the person skilled in the art may beapplied. Nitroanilines 3 may be hydrogenated under an atmosphere ofhydrogen at pressures between 1 bar and 100 bar in a suitable solventsuch as for example ethyl acetate, tetrahydrofurane, methanol or ethanoland in the presence of a metal catalyst such as for example palladium oncharcoal at temperatures between 0° C. and the boiling point of thesolvent, typically at room temperature. The addition of a suitable acidsuch as for example hydrochloric acid or acetic acid may be necessary.Alternatively, nitroanilines of general formula 3 may be reduced withiron/NH₄Cl or tin(II) chloride in a suitable solvent such as for examplewater, methanol or ethanol or mixtures thereof at temperatures betweenroom temperature and the boiling point of the solvent, typically at 70°C.

Nitroanilines of general formula 3 can be obtained from nitroarenes ofgeneral formula 1 by nucleophilic substitution with amines of generalformula 2 in a suitable solvent such as for example tetrahydrofurane andin the presence of a suitable base such as for example potassiumcarbonate or triethylamine at temperatures between room temperature andthe boiling point of the solvent, typically at 50-70° C. Instead ofusing amines of general formula 2 their corresponding ammonium salts canbe used as well. Nitroarenes 1 and amines 2 or their correspondingammonium salts are either commercially available, known compounds or maybe formed from known compounds by known methods by a person skilled inthe art.

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined supra.

An alternative route to nitroanilines of general formula 3 via reductiveamination is outlined in Scheme 2. Nitroanilines 4 may be reacted withcyclohexanones 5 in a suitable solvent such as for exampledichloromethane or dichloroethane and in the presence of a reducingagent such as for example sodium borohydride or sodiumtriacetoxyborohydride at temperatures between 0° C. and the boilingpoint of the solvent, typically at room temperature. It might benecessary to add an acid such as for example trifluoroacetic acid to thereaction mixture. Nitroanilines 4 and cyclohexanones 5 are eithercommercially available, known compounds or may be formed from knowncompounds by known methods by a person skilled in the art.

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined supra.

Suitably functionalized chlorobenzimidazoles (IV) may be reacted withanilines of general formula (V) in a suitable solvent such as forexample NMP at temperatures between room temperature and the boilingpoint of the solvent, typically at 110° C. Anilines (V) are eithercommercially available, known compounds or may be formed from knowncompounds by known methods by a person skilled in the art.

Chlorobenzimidazoles (IV) in turn can be obtained from benzimidazolonesof general formula 6 by reaction in chlorinating agents such as forexample phosphoric trichloride at temperatures between room temperatureand the boiling point of the reagent, typically at 105° C.Benzimidazolones of general formula 6 may be synthesized from suitablyfunctionalized diamines of general formula (II) by reaction withcarbonic acid equivalents such as for example CDI, phosgene or phosgenederivatives in a suitable solvent such as for example DMF ortetrahydrofurane at temperatures between room temperature and theboiling point of the solvent, typically at 50° C.

In accordance with an embodiment, the present invention also relates toa method of preparing a compound of general formula (I) as definedsupra, said method comprising the step of allowing an intermediatecompound of general formula (II):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra, to react with a compound ofgeneral formula (III):

in which R¹, R² and R³ are as defined as for the compound of generalformula (I), supra,

thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) supra.

In accordance with another embodiment, the present invention alsorelates to a method of preparing a compound of general formula (I) asdefined supra, said method comprising the step of allowing anintermediate compound of general formula (IV):

in which R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ are as defined for thecompound of general formula (I) supra,

to react with a compound of general formula (V):

in which R¹, R², R³ and R¹² are as defined as for the compound ofgeneral formula (I), supra,

thereby giving a compound of general formula (I):

in which R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are asdefined for the compound of general formula (I) supra.

General Part

All reagents, for which the synthesis is not described in theexperimental part, are either commercially available, or are knowncompounds or may be formed from known compounds by known methods by aperson skilled in the art.

The compounds and intermediates produced according to the methods of theinvention may require purification. Purification of organic compounds iswell known to the person skilled in the art and there may be severalways of purifying the same compound. In some cases, no purification maybe necessary. In some cases, the compounds may be purified bycrystallization. In some cases, impurities may be stirred out using asuitable solvent. In some cases, the compounds may be purified bychromatography, particularly flash column chromatography, using forexample prepacked silica gel cartridges, e.g. Biotage SNAP cartidgesKP-Sil® or KP-NH® in combination with a Biotage autopurifier system(SP4® or Isolera Four®) and eluents such as gradients of hexane/ethylacetate or DCM/methanol. In some cases, the compounds may be purified bypreparative HPLC using for example a Waters autopurifier equipped with adiode array detector and/or on-line electrospray ionization massspectrometer in combination with a suitable prepacked reverse phasecolumn and eluents such as gradients of water and acetonitrile which maycontain additives such as trifluoroacetic acid, formic acid or aqueousammonia.

In some cases, purification methods as described above can provide thosecompounds of the present invention which possess a sufficiently basic oracidic functionality in the form of a salt, such as, in the case of acompound of the present invention which is sufficiently basic, atrifluoroacetate or formate salt for example, or, in the case of acompound of the present invention which is sufficiently acidic, anammonium salt for example. A salt of this type can either be transformedinto its free base or free acid form, respectively, by various methodsknown to the persion skilled in the art, or be used as salts insubsequent biological assays. It is to be understood that the specificform (e.g. salt, free base etc.) of a compound of the present inventionas isolated and as described herein is not necessarily the only form inwhich said compound can be applied to a biological assay in order toquantify the specific biological activity.

UPLC-MS Standard Procedures

Analytical UPLC-MS was performed as described below. The masses (m/z)are reported from the positive mode electrospray ionisation unless thenegative mode is indicated (ES−). In most of the cases method A is used.If not, it is indicated.

UPLC-MS Method A

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm; Eluent A: water+0.1% formic acid, Eluent B:acetonitrile; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate0.8 mL/min; Temperature: 60° C.; Injection: 2 μL; DAD scan: 210-400 nm.

UPLC-MS Method B

Instrument: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEHC18 1.7 50×2.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min;Temperature: 60° C.; Injection: 2 μL; DAD scan: 210-400 nm; ELSD.

UPLC-MS Method C

Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C181.7 50×2.1 mm; Eluent A: water+0.05% formic acid, Eluent B:acetonitrile+0.05% formic acid; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min99% B; Flow rate 0.8 mL/min; Temperature: 60° C.; Injection: 2 μL; DADscan: 210-400 nm.

UPLC-MS Method D

Instrument: Waters Acquity UPLC-MS ZQ4000; Column: Acquity UPLC BEH C181.7 50×2.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min;Temperature: 60° C.; Injection: 2 μL; DAD scan: 210-400 nm; ELSD.

UPLC-MS Method E

Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C181.7 50×2.1 mm; Eluent A: water+0.1% formic acid, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min;Temperature: 60° C.; Injection: 1 μL; DAD scan: 210-400 nm; ELSD.

UPLC-MS Method F

Instrument: Waters Acquity UPLC-MS ZQ2000; Column: Acquity UPLC BEH C181.7 50×2.1 mm; Eluent A: water+0.2% ammonia, Eluent B: acetonitrile;Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate 0.8 mL/min;Temperature: 60° C.; Injection: 1 μL; DAD scan: 210-400 nm; ELSD.

UPLC-MS Method G

Instrument: Waters Acquity UPLC-MS; Column: XBridge BEH C18 2.5 μm2.1×50 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 2-98% B in 0.80 min, hold at 98% B to 1.30 min;Flow rate 0.8 mL/min; Detection: Waters Acquity Autosampler (UPLC LG 500nm).

UPLC-MS Method H

Instrument: Waters Acquity UPLC-MS; Column: XBridge BEH C18 2.5 μm2.1×50 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 2-98% B in 4.00 min, hold at 98% B to 4.70 min;Flow rate 0.8 mL/min; Detection: Waters Acquity Autosampler (UPLC LG 500nm).

LC-MS Standard Procedures

Analytical LC-MS was performed as described below. The masses (m/z) arereported from the positive mode electrospray ionisation unless thenegative mode is indicated (ES−).

LC-MS Method A

Instrument: Water Alliance 2695 HPLC Pump; Column: XBridge C18 2.5 μm2.1×20 mm; Eluent A: 10 mM ammonium bicarbonate pH 10, Eluent B:acetonitrile; Gradient: 0% B to 0.18 min, 0-95% B to 2.00 min, hold at95% B to 2.60 min; Flow rate 1 mL/min; Detection: Waters 996 PDA 215-350nm; Run Time: 3.10 min.

NMR peak forms are stated as they appear in the spectra, possible higherorder effects have not been considered.

The obtained benzimidazoles of general formula (I) may be chiral and maybe separated into their diastereomers and/or enantiomers by chiral HPLC.

INTERMEDIATES Intermediate 1-1 (±)3-fluoro-N¹-[(trans)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine and(±) 3-fluoro-N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine

Step 1: 3-fluoro-2-nitro-N-(3,3,5-trimethylcyclohexyl)aniline

10 g (62.86 mmol) 2,6-Difluoronitrobenzene (commercially available) and8.87 g (62.86 mmol) 3,3,5-trimethylcyclohexanamine (mixture ofstereoisomers, commercially available) were given in 178 mLtetrahydrofurane. After addition of 9.56 g (69.14 mmol) potassiumcarbonate the reaction mixture was heated at 50° C. overnight. Thereaction mixture was evaporated to dryness yielding a red oily residuewhich was diluted with ethyl acetate (400 mL). The organic phase wasextracted with water (100 mL) and brine (100 mL). After drying (sodiumsulfate) the solvent was evaporated yielding 18.6 g (>100%) of a darkredoil. 1.5 g of this crude material was purified for analytical reasons bycolumn chromatography (Biotage, eluents: hexane/ethylacetate) yielding1.35 g of the desired product (mixture of stereoisomers) which washowever still slightly contaminated.

UPLC-MS (Method B): R_(t)=1.65 min; m/z=281 (ES+, M+1).

Step 2: (±)3-fluoro-N¹-[(trans)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine and(±) 3-fluoro-N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine

18.5 g (65.99 mmol)3-Fluoro-2-nitro-N-(3,3,5-trimethylcyclohexyl)aniline from step 1 weredissolved in ethyl acetate (603 mL). After addition of 1.4 g (13.2 mmol)Pd/C the reaction mixture was stirred under a hydrogen atmosphereovernight at room temperature. The catalyst was filtered off via a glassfibre filter and washed with ethyl acetate. After evaporation of thesolvent 18.7 g (>100%) of the desired product (crude) were obtained.Purification by multiple column chromatography (Biotage, eluents:hexane/ethyl acetate) followed by a HPLC yielded 0.12 g of the puretrans diastereomer (as racemate) and 6.75 g of the pure cis diastereomer(as racemate). In addition 3.28 g of a material was isolated whichcontains mainly the cis diastereomer and 3.7% of the trans diastereomer.

UPLC-MS (Method B): R_(t)=1.49 and 1.55 min; m/z=251 each (ES+, M+1).

Intermediate 1-2 (±)4-bromo-N-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine

Step 1: 4-bromo-2-nitro-N-(3,3,5-trimethylcyclohexyl)aniline

17 g (77.27 mmol) 4-Bromo-1-fluoro-2-nitrobenzene (commerciallyavailable) were given in 308 mL tetrahydrofurane. After addition of11.75 g (84.99 mmol) potassium carbonate the reaction mixture wasstirred for 10 min at room temperature. 10.92 g (77.27 mmol)3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commerciallyavailable) were added and the reaction mixture was heated at 50° C.overnight. The reaction mixture was diluted with ethyl acetate andwater. The aqueous phase was reextracted twice with ethyl acetate andthe combined organic extracts were dried (sodium sulfate). The solventwas evaporated yielding 28.3 g (97%) of the desired product as a mixtureof stereoisomers.

UPLC-MS: R_(t)=1.78 min; m/z=341 (ES+, M+1).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.72-1.03 (m, 11H), 1.13 (t, 1H),1.29-1.39 (m, 1H), 1.59-1.89 (m, 2H), 1.91-2.05 (m, 1H), 3.70-3.90 (m,1H), 7.12 (d, 1H), 7.64 (dd, 1H), 7.82 (d, 1H), 8.15 (d, 1H).

Step 2: (±)4-bromo-N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine

28.3 g (82.93 mmol) of the crude product of step 1,4-bromo-2-nitro-N-(3,3,5-trimethylcyclohexyl)aniline, were dissolved inmethanol (366 mL). After addition of 66.83 g (290 mmol) tin(II)chloridedihydrate the reaction mixture was stirred for 12 hours at 70° C. Thereaction mixture was evaporated to dryness and the residue was dilutedwith ethyl acetate. After washing with water and brine the organic phasewas dried and the solvent was removed. Purification of the residue bycolumn chromatography (eluents: hexane/ethyl acetate) yielded 27 g (99%)of the title compound.

UPLC-MS: R_(t)=1.54 min; m/z=311 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.72-1.02 (m, 11H), 1.09-1.21 (m,1H), 1.29-1.39 (m, 1H), 1.54-1.75 (m, 2H), 1.85-2.02 (m, 1H), 3.40-3.60(m, 1H), 6.74-6.92 (m, 2H), 6.99 (d, 1H).

Intermediate 1-3 (±) tert-butyl(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenoxy)-acetate

Step 1: tert-butyl (4-fluoro-3-nitrophenoxy)acetate

10 g (63.65 mmol) 4-Fluoro-3-nitrophenol were dissolved in 50 mLN,N-dimethylformamide. After addition of 2.8 g (70.02 mmol) sodiumhydride (60% in mineral oil) the reaction mixture was stirred for 20′.12.54 g (63.65 mmol) tert-Butyl bromoacetate were added and stirring wascontinued at room temperature overnight. The reaction mixture wasdiluted with sodium bicarbonate. After extraction with methyl-tert-butylether (trice) the combined organic phases were evaporated to drynessyielding the product contaminated with starting material. Therefore,methyl-tert. butylether was added and the mixture was extracted with 1NNaOH. The organic phase was washed with brine and dried (sodiumsulfate). After evaporation of the solvent 18.06 g (>100%) of thedesired product (slightly contaminated) were obtained, which was used inthe next step without further purification.

Step 2: tert-butyl {3-nitro-4-[(3,3,5-trimethylcyclohexyl)amino]phenoxy}-acetate

10 g (36.87 mmol) tert-Butyl (4-fluoro-3-nitrophenoxy)acetate from step1 and 5.21 g (36.87 mmol) 3,3,5-trimethylcyclohexanamine (mixture ofstereoisomers, commercially available) were given in 105 mLtetrahydrofurane. After addition of 6.11 g (44.20 mmol) potassiumcarbonate the reaction mixture was stirred at 50° C. for 96 hours. Dueto an incomplete reaction additional 0.2 eq amine and potassiumcarbonate were added and stirring at 50° C. was continued for threehours. The reaction mixture was evaporated to dryness and the residuewas diluted with water. After extraction with ethyl acetate (trice) thecombined organic phases were washed with brine and dried (sodiumsulfate). The solvent was evaporated yielding 13 g (81%) of the desired,however contaminated product which was used without further purificationin the next step.

UPLC-MS: R_(t)=1.72 min; m/z=393 (ES+, M+1).

Step 3: (±) tert-butyl(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenoxy)-acetate

13 g (33.12 mmol) tert-Butyl{3-nitro-4-[(3,3,5-trimethylcyclohexyl)amino]phenoxy}-acetate from step2 were dissolved in ethyl acetate (104 mL). After addition of 0.70 g(6.62 mmol) Pd/C the reaction mixture was stirred under a hydrogenatmosphere at room temperature for 24 hours. The catalyst was filteredoff via a glass fibre filter and washed with ethyl acetate. Afterevaporation of the solvent 15 g (>100%) of the desired product (crude)were obtained. Purification by multiple column chromatographies(Biotage, eluents: hexane/ethyl acetate) yielded 7.65 g (62%) of thetitle compound.

UPLC-MS (Method B): R_(t)=1.59 min; m/z=363 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.79-0.98 (m, 11H), 1.27-1.45 (m,11H), 1.56-1.70 (m, 2H), 1.87-1.99 (m, 1H), 3.21 (br. s., 1H), 3.60 (d.,1H), 4.37 (s, 2H), 4.59 (s, 2H), 5.98 (dd, 1H), 6.16 (d, 1H), 6.35 (d,1H).

Intermediate 1-4 (±) methyl3-amino-4-{[(trans)-3,3,5-trimethylcyclohexyl]amino}benzoate and (±)methyl 3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate

Step 1: methyl 3-nitro-4-[(3,3,5-trimethylcyclohexyl)amino]benzoate

22.7 g (113.99 mmol) Methyl-4-fluoro-3-nitrobenzoate (commerciallyavailable) and 16.1 g (113.99 mmol) 3,3,5-trimethylcyclohexanamine(mixture of stereoisomers, commercially available) were given in 460 mLtetrahydrofurane. After addition of 17.34 g (125.39 mmol) potassiumcarbonate the reaction mixture was heated at 50° C. for 45 hours. Thesolids were filtered off via a glass fibre filter, washed with ethylacetate and discarded. The filtrate was diluted with water (200 mL) andethyl acetate (450 mL). After vigorous stirring for 15 min the organicphase was separated. The aqueous phase was washed with ethyl acetate(250 mL). The combined organic extracts were washed with water (150 mL)and brine (150 mL). After drying (sodium sulfate) the solvent wasevaporated yielding 35.9 g (93%) of an orangeyellow solid (mixture ofstereoisomers) which was used without further purification in the nextstep.

UPLC-MS: R_(t)=1.67 min; m/z=321 (ES+, M+1).

Step 2: methyl3-amino-4-{[(trans)-3,3,5-trimethylcyclohexyl]amino}benzoate and methyl3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate

15 g (46.82 mmol) Methyl3-nitro-4-[(3,3,5-trimethylcyclohexyl)amino]benzoate from step 1 weredissolved in ethyl acetate (706 mL). After addition of 0.98 g (9.18mmol) Pd/C the reaction mixture was stirred under a hydrogen atmospherefor seven hours at room temperature. The catalyst was filtered off via aglass fibre filter and washed with ethyl acetate. After evaporation ofthe solvent the residue was purified by column chromatography (Biotage,eluents: hexane/ethyl acetate) yielding 0.6 g (4.2%) of the transdiastereomer (as racemate) and 9.99 g (70%) of the cis diastereomer (asracemate).

Trans: ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.81-0.97 (m, 10H), 1.21-1.33(m, 2H), 1.38 (d, 1H), 1.62 (d, 1H), 1.72 (d, 1H), 1.99-2.13 (m, 1H),3.68-3.78 (br., 4H), 4.74 (br., 3H), 6.42 (d, 1H), 7.14-7.24 (m, 2H).

Cis: ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.68-1.06 (m, 12H), 1.35 (d,1H), 1.62-1.79 (m, 2H), 1.91-2.03 (m, 1H), 3.42-3.57 (m, 1H), 3.70 (s,3H), 4.72 (s, 2H), 4.82 (d, 1H), 6.45 (d, 1H), 7.11-7.22 (m, 2H).

Intermediate 1-5 (±)N¹-[(trans)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine and (±)N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine

Intermediate 1-5 was synthesized in analogy to intermediate 1-1.

Trans: ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.84-0.97 (m, 7H), 0.98 (s,3H), 1.19-1.42 (m, 3H), 1.56-1.65 (m, 1H), 1.71 (d, 1H), 1.90-2.10 (m,1H), 3.58-3.65 (m, 1H), 3.93 (d, 1H), 4.39 (s, 2H), 6.34-6.45 (m, 2H),6.45-6.60 (m, 2H).

Cis: ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.60-1.00 (m, 12H), 1.32 (d,1H), 1.56-1.75 (m, 2H), 1.95 (d, 1H), 3.25-3.41 (m, 1H), 3.98 (d, 1H),4.41 (s, 2H), 6.27-6.52 (m, 4H).

Intermediate 1-9 (±) tert-butyl4-(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenoxy)butanoate

Intermediate 1-9 was synthesized in analogy to intermediate 1-3.

UPLC-MS: R_(t)=1.23 min; m/z=391 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.57-0.96 (m, 10H), 1.32 (d, 1H),1.40 (s, 9H), 1.55-1.73 (m, 2H), 1.76-2.00 (m, 3H), 2.30 (t, 2H),3.12-3.27 (m, 1H), 3.52 (d, 1H), 3.75 (t, 2H), 4.54 (s, 2H), 5.96-6.07(m, 1H), 6.17 (d, 1H), 6.36 (d, 1H).

Intermediate 1-14tert-butyl{3-amino-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenoxy}acetate

Intermediate 1-14 was synthesized in analogy to intermediate 1-3.

¹H-NMR (400 MHz, DMSO-d₆) δ [ppm]=0.88 (s, 6H), 0.86-1.27 (m, 4H), 1.04(s, 6H), 1.41 (s, 9H), 1.70 (br. d, 2H), 3.36 (me, 1H), 3.61 (br. d,1H), 4.37 (s, 2H), 4.58 (br. s., 2H), 6.00 (m, 1H), 6.18 (d, 1H), 6.34(d, 1H).

LC-MS (Method B): R_(t)=1.60 min; MS (ES+, M+1): 377.

Intermediate 1-19 tert-butyl{3-amino-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}carbamate

Step 1: tert-butyl{3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}carbamate

A solution of tert-butyl (4-fluoro-3-nitrophenyl)carbamate (CAS No.[332370-72-6]; 1.08 g, 4.22 mmol) in THF (17 mL) was treated withpotassium carbonate (2.00 eq., 1.17 g, 8.43 mmol) and3,3,5,5-tetramethylcyclohexanamine hydrochloride (commerciallyavailable; 1.00 eq., 0.808 g, 4.22 mmol) and stirred at 60° C. for fourdays. The reaction mixture was filtered, the filtrate partitionedbetween water and ethyl acetate and extracted with ethyl acetate. Thecombined organic layers were washed with water, brine, dried with sodiumsulfate and concentrated in vacuo. The obtained red oil was purified byflash chromatography (SiO₂-hexane/ethyl acetate) to give the titlecompound (971 mg, 58%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.92 (s, 6H), 1.06-1.14 (m, 9H),1.25-1.28 (m, 1H), 1.47 (s, 9H), 1.75-1.78 (m, 2H), 3.82-3.91 (m, 1H),7.04 (d, 1H), 7.54 (dd, 1H), 7.74 (d, 1H), 8.33 (br. s., 1H), 9.34 (br.s., 1H).

UPLC-MS (ESI+): [M+H]⁺=392; R_(t)=1.72 min.

Step 2: tert-butyl{3-amino-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}carbamate

A solution of tert-butyl{3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}carbamate (960mg, 2.45 mmol) from step 1 in ethyl acetate (43 mL) was treated withPd/C (10 wt %; 0.25 eq., 65 mg, 0.61 mmol) and stirred under a hydrogenatmosphere at rt overnight. The reaction mixture was filtrated overCelite, washed with ethyl acetate and the filtrate concentrated invacuo. The obtained oil was purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the title compound (681 mg, 76%).¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.87-0.93 (m, 8H), 1.04-1.08 (m, 7H),1.23-1.27 (m, 1H), 1.44 (s, 9H), 1.70-1.73 (m, 2H), 3.36-3.45 (m, 1H),3.70-3.72 (m, 1H), 4.48 (br. s., 2H), 6.34 (d, 1H), 6.47 (dd, 1H), 6.74(br. s., 1H), 8.63 (br. s., 1H).

UPLC-MS (ESI+): [M+H]⁺=362; R_(t)=1.23 min.

Intermediate 1-21 (±) methyl2-chloro-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazole-5-carboxylate

Step 1: methyl2-oxo-1-[(cis)-3,3,5-trimethylcyclohexyl]-2,3-dihydro-1H-benzimidazole-5-carboxylate

A solution of methyl3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (intermediate1-4; 3.43 g, 11.8 mmol) in DMF (100 mL) was treated withdi-1H-imidazol-1-ylmethanone (CAS-No. [530-62-1]; 1.4 eq., 2.7 g, 17mmol) and stirred at 50° C. for 2 h. The reaction mixture was cooled tort, poured onto water and stirred for 15 minutes. The formed precipitatewas filtered off, washed with water and dried in vacuo to give the titlecompound (3.2 g, 83%) which was used without further purification.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.01 (m, 10H), 1.34-1.39 (m,2H), 1.67-1.82 (m, 3H), 1.96 (t, 1H), 3.82 (s, 3H), 4.35-4.46 (m, 1H),7.40 (d, 1H), 7.50 (d, 1H), 7.65 (dd, 1H), 11.15 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=317; R_(t)=1.32 min.

Step 2: (±) methyl2-chloro-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazole-5-carboxylate

A solution of methyl2-oxo-1-[(cis)-3,3,5-trimethylcyclohexyl]-2,3-dihydro-1H-benzimidazole-5-carboxylate(1.00 g, 3.16 mmol) from step 1 in phosphoric trichloride (5.4 eq., 1.6mL, 17 mmol) was heated to reflux for 4 h, cooled to rt and stirring wascontinued at rt overnight. The reaction mixture was poured ontoice-cooled water, basified with 2 M aqueous sodium hydroxide andextracted with ethyl acetate. The combined organic layers were washedwith brine, dried with sodium sulfate and concentrated in vacuo. Theobtained material was purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the title compound (838 mg, 78%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.94-1.00 (m, 6H), 1.06-1.13 (m, 4H),1.41 (d, 1H), 1.53-1.57 (m, 1H), 1.80-1.90 (m, 3H), 2.02 (t, 1H), 3.87(s, 3H), 4.68-4.79 (m, 1H), 7.87 (dd, 1H), 7.96 (d, 1H), 8.17 (d, 1H).

UPLC-MS (ESI+): [M+H]⁺=335/337 (CI isotope pattern); R_(t)=1.55 min.

Intermediate 1-22 methyl3-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

Step 1: 4-amino-2-methyl-3-nitrobenzoic acid and4-amino-2-methyl-5-nitrobenzoic acid

A suspension of 4-acetamido-2-methylbenzoic acid (CAS No. [103204-69-9];20.0 g, 104 mmol) in concentrated sulfuric acid was cooled to 0° C. andtreated dropwise with a mixture of fuming nitric acid (1.05 eq., 4.51mL, 109 mmol) and concentrated sulfuric acid (1.85 eq., 10.5 mL, 192mmol). The reaction mixture was warmed to rt and stirred for 1 h. It waspoured in small portions on ice water, the formed orange precipitatefiltered off and air-dried to give a mixture of4-amino-2-methyl-3-nitrobenzoic acid and 4-amino-2-methyl-5-nitrobenzoicacid (ca 2:3, 17 g, 84%) which was used in the next step without furtherpurification.

¹H-NMR (300 MHz, DMSO-d₆, major isomer): δ [ppm]=2.46 (s, 3H), 6.82 (s,1H), 8.58 (s, 1H) [minor isomer: 2.38 (s, 3H), 6.74 (d, 1H), 7.73 (d,1H)].

UPLC-MS (ESI+): [M+H]⁺=197; R_(t)=0.73 min.

Step 2: methyl 4-amino-2-methyl-3-nitrobenzoate and methyl4-amino-2-methyl-5-nitrobenzoate

A mixture of 4-amino-2-methyl-3-nitrobenzoic acid and4-amino-2-methyl-5-nitrobenzoic acid (ca 2:3; 40.6 g, 207 mmol) fromstep 1 in methanol (323 mL) was treated dropwise with concentratedsulfuric acid (9.5 eq., 105 mL, 2.0 mol) and stirred at 60° C. for 7 h.The reaction mixture was poured on ice water, the formed precipitatefiltered off and washed with cold water. The obtained material was driedin vacuo at 40° C. overnight to give a mixture of methyl4-amino-2-methyl-3-nitrobenzoate and methyl4-amino-2-methyl-5-nitrobenzoate (ca 2:3, 44 g, quant.) which was usedin the next step without further purification.

¹H-NMR (300 MHz, DMSO-d₆, major isomer): δ [ppm]=2.46 (s, 3H), 3.78 (s,3H), 6.84 (s, 1H), 7.83 (br. s., 2H), 8.58 (s, 1H) [minor isomer: 2.37(s, 3H), 3.75 (s, 3H), 6.51 (br. s., 2H), 6.75 (d, 1H), 7.73 (d, 1H)].

UPLC-MS (ESI+): [M+H]⁺=211; R_(t)=1.00 min.

Step 3: methyl2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate andmethyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

A mixture of methyl 4-amino-2-methyl-3-nitrobenzoate and methyl4-amino-2-methyl-5-nitrobenzoate (ca 2:3; 1.00 g, 4.76 mmol) from step 2and 3,3,5,5-tetramethylcyclohexanone (CAS No. [14376-79-5]; 1.00 eq.,734 mg, 4.76 mmol) in 1,2-dichloroethane (10 mL) was treated dropwisewith trifluoroacetic acid (5 mL) and stirred at rt for 5 minutes uponwhich sodium triacetoxyborohydride ([56553-60-7]; 1.5 eq., 1.5 g, 7.1mmol) were added in portions and stirring at rt was continued for 2days. An additional amount of trifluoroacetic acid (1 mL) and sodiumtriacetoxyborohydride (1.0 eq., 1.0 g, 4.8 mmol) were added and stirringat rt was continued for 6 days. The ice-cooled reaction mixture wasquenched with an aqueous ammonia solution (25%) and partitioned betweenwater and dichloromethane. The phases were separated and the aqueousphase extracted with dichloromethane. The combined organic layers weredried with magnesium sulfate and concentrated in vacuo. The obtainedmaterial was purified by flash chromatography (SiO₂-hexane/ethylacetate) to give a mixture of methyl2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate andmethyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate(ca 4:1, 667 mg, 39%).

¹H-NMR (400 MHz, DMSO-d₆, major isomer): δ [ppm]=0.89-1.17 (m, 14H),1.20-1.29 (m, 2H), 1.59-1.62 (m, 2H) [minor isomer: 1.74-1.77 (m, 2H)],2.36 (s, 3H) [minor isomer: 2.57 (s, 3H)], 3.65-3.74 (m, 1H), 3.77 (s,3H) [minor isomer: 3.80 (s, 3H)], 5.98 (d, 1H), 6.81 (d, 1H), 7.84 (d,1H) [minor isomer: 6.93 (s, 1H), 8.05 (d, 1H), 8.66 (s, 1H)].

UPLC-MS (ESI+): [M+H]⁺=349; R_(t)=1.73/1.76 min.

Step 4: methyl3-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

A mixture of methyl2-methyl-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate andmethyl 2-methyl-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate(ca 4:1; 660 mg, 1.89 mmol) from step 3 in ethyl acetate (30 mL) wastreated with Pd/C (10 wt %; 0.25 eq., 50 mg, 0.47 mmol) and stirredunder a hydrogen atmosphere at rt overnight. The reaction mixture wasfiltrated over Celite, washed with ethyl acetate and the filtrateconcentrated in vacuo. The obtained regioisomeric mixture was purifiedby flash chromatography (SiO₂-hexane/ethyl acetate) to give methyl3-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate(intermediate 1-22; 357 mg, 59%) along with the minor isomer methyl5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclo-hexyl)amino]benzoate(intermediate 1-24; 111 mg, 17%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.91 (s, 6H), 1.01 (t, 2H), 1.07-1.09(m, 7H), 1.25-1.29 (m, 1H), 1.72-1.75 (m, 2H), 2.30 (s, 3H), 3.56-3.65(m, 1H), 3.69 (s, 3H), 4.44 (br. s., 2H), 4.84 (d, 1H), 6.37 (d, 1H),7.17 (d, 1H).

UPLC-MS (ESI+): [M+H]⁺=319; R_(t)=1.55 min.

Intermediate 1-27 methyl3-amino-2-fluoro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

Step 1:4-bromo-3-fluoro-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline

In analogy to step 3 of intermediate 1-22:4-Bromo-3-fluoro-2-nitroaniline (CAS No. [886762-75-0]; 5.80 g, 24.7mmol) and 3,3,5,5-tetramethylcyclohexanone (CAS No. [14376-79-5]; 1.00eq., 3.81 g, 24.7 mmol) were reacted with trifluoroacetic acid (20 mL)and sodium triacetoxyborohydride ([56553-60-7]; 1.5 eq., 7.85 g, 37.0mmol) in dichloromethane (60 mL) at rt for 2 days to give after flashchromatography (SiO₂-hexane/ethyl acetate) the title compound (4.7 g,48%) along with reisolated 4-bromo-3-fluoro-2-nitroaniline (2.7 g, 47%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90 (s, 6H), 1.06-1.15 (m, 9H),1.23-1.27 (m, 1H), 1.66-1.70 (m, 2H), 3.71-3.84 (m, 1H), 5.98 (d, 1H),6.81 (dd, 1H), 6.85 (d, 1H), 7.68 (dd, 1H).

UPLC-MS (ESI+): [M+H]⁺=373/375; R_(t)=1.78 min (Br isotope pattern).

Step 2: methyl3-amino-2-fluoro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

A solution of4-bromo-3-fluoro-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline (2.08g, 5.57 mmol) from step 1 in methanol (56 mL) was placed into a steelautoclave under argon atmosphere.1,1′-Bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (CAS No. [95464-05-4]; 0.200 eq., 910 mg, 1.11mmol) and potassium acetate (4.00 eq., 2.19 g, 22.3 mmol) were added andthe mixture was purged 3 times with carbon monoxide. The mixture wasstirred for 30 minutes at 20° C. under a carbon monoxide pressure of ca12.6 bar. The autoclave was set under vacuum again, then a carbonmonoxide pressure of ca 12 bar was applied and the mixture heated to100° C. for 21 h, yielding a maximum pressure of ca 13.3 bar. Thereaction was cooled to rt, the pressure released and the reactionmixture concentrated in vacuo. The obtained crude product was purifiedby flash chromatography (SiO₂-hexane/ethyl acetate) to give the desiredester (805 mg, 44%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.91 (s, 6H), 0.97-1.10 (m, 9H),1.25-1.29 (m, 1H), 1.70-1.74 (m, 2H), 3.58-3.68 (m, 1H), 3.73 (s, 3H),4.64 (br. s., 2H), 5.22 (d, 1H), 6.32 (d, 1H), 7.11 (t, 1H).

UPLC-MS (ESI+): [M+H]⁺=323; R_(t)=1.51 min.

Intermediate 1-28 methyl3-amino-2-methoxy-4-[(3,3,5,5-tetramethylcyclohexyl)amino]benzoate

Step 1:4-bromo-3-methoxy-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline

4-Bromo-3-fluoro-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline(prepared in step 1 of intermediate 1-27; 3.50 g, 9.38 mmol) was treatedwith a solution of sodium methanolate in methanol (CAS No. [124-41-4];18 eq., 38 mL of a 30 wt % solution) and stirred at rt overnight. Thesuspension was taken up with ethyl acetate and washed with water. Thephases were separated and the organic layer concentrated in vacuo. Theobtained material (3.44 g, 93%) was taken to the next step withoutfurther purification.

UPLC-MS (ESI+): [M+H]⁺=385/387; R_(t)=1.79 min (Br isotope pattern).

Step 2: methyl3-amino-2-methoxy-4-[(3,3,5,5-tetramethylcyclo-hexyl)amino]benzoate

In analogy to step 2 from intermediate 1-27:4-Bromo-3-methoxy-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline (3.44g, 8.75 mmol) from step 1 was reacted with1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloridedichloromethane complex (CAS No. [95464-05-4]; 0.2 eq., 1.43 g, 1.75mmol) and potassium acetate (4.00 eq., 3.44 g, 35.0 mmol) in methanol(110 mL) in a steel autoclave under a carbon monoxide pressure of ca 16bar at 100° C. for 22 h, yielding a maximum pressure of ca 18 bar. Theobtained crude product was purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the desired ester (1.20 g, 39%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.91 (s, 6H), 0.97-1.09 (m, 9H),1.25-1.29 (m, 1H), 1.71-1.75 (m, 2H), 3.55-3.65 (m, 4H), 3.71 (s, 3H),4.48 (br. s., 2H), 4.97 (d, 1H), 6.29 (d, 1H), 7.10 (d, 1H).

UPLC-MS (ESI+): [M+H]⁺=335; R_(t)=1.52 min.

Intermediate 1-31 (±) methyl5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate

Step 1: (±) methyl2-fluoro-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and(±) methyl 4-fluoro-5-nitro-2-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate

A solution of methyl 2,4-difluoro-5-nitrobenzoate (CAS No.[125568-71-0]; 15.7 g, 72.3 mmol) in acetonitrile (360 mL) was treatedwith triethylamine (1.30 eq., 13.1 mL, 94.0 mmol) and3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commerciallyavailable; 1.40 eq., 14.3 g, 101 mmol) and stirred at room temperatureovernight. The reaction mixture was diluted with water (300 mL) and thepH of the mixture was adjusted to pH 3 by addition of aqueous HCl (2M).The reaction mixture was extracted with ethyl acetate and the combinedorganic layers were washed with water, brine, dried with sodium sulfateand concentrated in vacuo to give a mixture of (±) methyl2-fluoro-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and(±) methyl4-fluoro-5-nitro-2-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca78:22, 33.5 g, quant.). The material (which contained minor amounts ofthe corresponding trans-products) was used in the next step withoutfurther purification.

UPLC-MS (ESI+): [M+H]⁺=339; R_(t)=1.72/1.76 min.

Step 2: (±) methyl2-methoxy-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate

In analogy to step 1 of intermediate 1-28: An ice-cooled mixture of (±)methyl2-fluoro-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate and(±) methyl4-fluoro-5-nitro-2-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate (ca78:22; 7.00 g, 16.5 mmol) from step 1 in methanol (15 mL) was slowlytreated with a solution of sodium methanolate in methanol (CAS No.[124-41-4]; 10 eq., 38 mL of a 30 wt % solution) and stirred at 0° C.for 1 hour. The suspension was taken up with ethyl acetate and washedwith water. The phases were separated, the organic layer dried withsodium sulfate and concentrated in vacuo. The obtained material waspurified by flash chromatography (SiO₂-hexane/ethyl acetate) to give thetitle compound (2.9 g, 50%) as racemic cis diastereomer.

UPLC-MS (ESI+): [M+H]⁺=351; R_(t)=1.57 min.

Step 3: (±) methyl5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate

In analogy to step 2 of intermediate 1-19: (±) Methyl2-methoxy-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate(2.07 g, 5.26 mmol) from step 2 was hydrogenated with Pd/C (10 wt %;0.250 eq., 140 mg, 1.31 mmol) and hydrogen gas in ethyl acetate (80 mL)at rt overnight to give the title compound (1.9 g, quant.) which wasused in the next step without further purification.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.73-0.82 (m, 2H), 0.90 (d, 3H),0.93-0.99 (m, 4H), 1.01 (s, 3H), 1.36-1.39 (m, 1H), 1.71-1.82 (m, 2H),1.95-1.99 (m, 1H), 3.47-3.58 (m, 1H), 3.65 (s, 3H), 3.69 (s, 3H), 4.29(br. s., 2H), 4.91 (d, 1H), 6.10 (s, 1H), 7.03 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=321; R_(t)=1.26 min (Method E).

Intermediate 1-32 (±) methyl3-(5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate

Step 1: 1-bromo-4-fluoro-2-methoxy-5-nitrobenzene

A mixture of 1-bromo-4-fluoro-2-methoxybenzene (CAS No. [450-88-4]; 10.0g, 48.8 mmol) in concentrated sulfuric acid (50 mL) was cooled to 0° C.and treated dropwise with a freshly prepared mixture of fuming nitricacid (1.05 eq., 2.1 mL, 51 mmol) and concentrated sulfuric acid (1.85eq., 4.8 mL, 90 mmol). The reaction mixture was stirred at 0° C. for 30minutes and poured in small portions on ice water. The formedprecipitate was filtered off, washed with cold water and kept. Thefiltrate was extracted with ethyl acetate and the organic layer combinedwith the isolated precipitation. The organic layer was dried with sodiumsulfate and concentrated in vacuo. The obtained material was purified byflash chromatography (SiO₂-hexane/ethyl acetate) to give the titlecompound (5.88 g, 44%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=4.00 (s, 3H), 7.44 (d, 1H), 8.40 (d,1H). UPLC-MS (ESI−): [M−H]⁻=248/250; R_(t)=1.17 min (Br isotope pattern;Method E).

Step 2: (±)4-bromo-5-methoxy-2-nitro-N-[(cis)-3,3,5-trimethylcyclohexyl]aniline

In analogy to step 1 of intermediate 1-19:1-Bromo-4-fluoro-2-methoxy-5-nitrobenzene (2.90 g, 11.6 mmol) from step1 was reacted with potassium carbonate (1.10 eq., 1.76 g, 12.8 mmol) and3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commerciallyavailable; 1.00 eq., 1.64 g, 11.6 mmol) in THF (87 mL) at 70° C.overnight to give the title compound (4.39 g, 97%) as a racemic mixtureof cis diastereomer (ca 92-94%) and trans diastereomer (ca 6-8%) whichwas not further purified.

¹H-NMR (400 MHz, DMSO-d₆, cis isomer): δ [ppm]=0.81-0.94 (m, 8H), 1.04(s, 3H), 1.08 (t, 1H), 1.35-1.38 (m, 1H), 1.76-1.79 (m, 2H), 2.02-2.05(m, 1H), 3.83-3.93 (m, 1H), 3.98 (s, 3H), 6.44 (s, 1H), 8.14 (br. d.,1H), 8.22 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=371/373; R_(t)=1.72 min (Br isotope pattern;Method E).

Step 3: (±) methyl(2E)-3-(2-methoxy-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)prop-2-enoate

To a solution of (±)4-bromo-5-methoxy-2-nitro-N-[(cis)-3,3,5-trimethylcyclohexyl]aniline(6.79 g, 17.4 mmol) from step 2 in DMF (129 mL) were added methylprop-2-enoate (CAS No. [96-33-3]; 3.00 eq., 4.69 mL, 52.1 mmol) andtriethylamine (2.00 eq., 4.84 mL, 34.7 mmol). The mixture was purgedwith argon several times and stirred at rt for 10 minutes.Tetrakis(triphenylphosphine)palladium (0.150 eq., 3.01 g, 2.61 mmol) wasadded, the mixture purged with argon again and heated to 110° C.overnight. The reaction mixture was cooled to rt and diluted with water.It was extracted with ethyl acetate (3 times) and the combined organiclayers were washed with brine, dried with sodium sulfate andconcentrated in vacuo. The obtained material was purified by flashchromatography (SiO₂-hexane/ethyl acetate) to give the title compound(3.9 g, 55%) as racemic cis diastereomer.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.80-0.94 (m, 8H), 1.04 (s, 3H), 1.11(t, 1H), 1.35-1.39 (m, 1H), 1.76-1.80 (m, 2H), 2.01-2.05 (m, 1H), 3.69(s, 3H), 3.85-3.96 (m, 1H), 4.00 (s, 3H), 6.39 (s, 1H), 6.53 (d, 1H),7.66 (d, 1H), 8.27 (br. d., 1H), 8.40 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=377; R_(t)=1.68 min (Method E).

Step 4: (±) methyl3-(5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate

In analogy to step 2 of intermediate 1-19: A solution of (±) methyl(2E)-3-(2-methoxy-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)prop-2-enoate(2.70 g, 7.17 mmol) from step 3 in ethyl acetate (190 mL) was treatedwith Pd/C (10 wt %; 1.50 eq., 1.15 g, 10.8 mmol) and stirred under ahydrogen atmosphere at rt overnight. Due to incomplete conversionanother amount of Pd/C (10 wt %; 0.50 eq., 382 mg, 3.59 mmol) was addedand stirring under a hydrogen atmosphere at rt continued for one day.The reaction mixture was filtrated over Celite, washed with ethylacetate and the filtrate concentrated in vacuo to give the titlecompound (2.34 g, 84%) as racemic cis diastereomer which was not furtherpurified.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.66-0.74 (m, 1H), 0.77 (t, 1H),0.85-0.91 (m, 7H), 0.99 (s, 3H), 1.34-1.37 (m, 1H), 1.70-1.73 (m, 2H),1.94-1.97 (m, 1H), 2.40-2.44 (m, 2H), 2.58-2.62 (m, 2H), 3.33-3.41 (m,1H), 3.57 (s, 3H), 3.65 (s, 3H), 3.94 (br. d., 1H), 4.00 (br. s., 2H),6.13 (s, 1H), 6.33 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=349; R_(t)=1.49 min (Method F).

Intermediate 1-33 (±) methyl3-(5-amino-2-methyl-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate

Step 1: (±)4-bromo-5-methyl-2-nitro-N-[(cis)-3,3,5-trimethylcyclohexyl]aniline

In analogy to step 1 of intermediate 1-19:1-Bromo-4-fluoro-2-methyl-5-nitrobenzene (CAS No. [170098-98-3]; 1.00eq., 3.60 g, 15.4 mmol) was reacted with potassium carbonate (1.10 eq.,2.34 g, 16.9 mmol) and 3,3,5-trimethylcyclohexanamine (mixture ofstereoisomers, commercially available; 1.00 eq., 2.17 g, 15.4 mmol) inTHF (110 mL) at rt for 7 days and at 40° C. for 3 hours to give afterpurification by flash chromatography (SiO₂-hexane/ethyl acetate) thetitle compound (5.1 g, 84%) as a racemic mixture of cis diastereomer (ca90%) and trans diastereomer (ca 7%).

¹H-NMR (300 MHz, DMSO-d₆, cis isomer): δ [ppm]=0.72-0.89 (m, 5H), 0.94(s, 3H), 1.01 (s, 3H), 1.13 (t, 1H), 1.33-1.37 (m, 1H), 1.65-1.87 (m,2H), 1.98-2.02 (m, 1H), 2.37 (s, 3H), 3.75-3.88 (m, 1H), 7.16 (s, 1H),7.82 (br. d., 1H), 8.16 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=355/357; R_(t)=1.84 min (Br isotope pattern;Method E).

Step 2: (±) methyl(2E)-3-(2-methyl-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)prop-2-enoate

In analogy to step 3 of intermediate 1-32: (±)4-Bromo-5-methyl-2-nitro-N-[(cis)-3,3,5-trimethylcyclohexyl]aniline(2.41 g, 6.78 mmol) from step 1 was reacted with methyl prop-2-enoate(CAS No. [96-33-3]; 3.00 eq., 1.83 mL, 20.4 mmol), triethylamine (2.00eq., 1.89 mL, 13.6 mmol) and tetrakis(triphenylphosphine)palladium(0.150 eq., 1.18 g, 1.02 mmol) in DMF (48 mL) at 110° C. overnight togive after purification by flash chromatography (SiO₂-hexane/ethylacetate) the title compound (1.81 g, 73%) as racemic cis diastereomer.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.75-0.94 (m, 8H), 1.02 (s, 3H), 1.15(t, 1H), 1.34-1.38 (m, 1H), 1.67-1.86 (m, 2H), 1.99-2.02 (m, 1H), 2.42(s, 3H), 3.71 (s, 3H), 3.81-3.91 (m, 1H), 6.43 (d, 1H), 7.02 (s, 1H),7.69 (d, 1H), 7.98 (br. d., 1H), 8.38 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=361; R_(t)=1.72 min (Method E).

Step 4: (±) methyl3-(5-amino-2-methyl-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate

In analogy to step 2 of intermediate 1-19: A solution of (±) methyl(2E)-3-(2-methyl-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)prop-2-enoate(1.81 g, 5.02 mmol) from step 2 in a mixture of ethanol (100 mL) andethyl acetate (30 mL) was treated with Pd/C (10 wt %; 1.50 eq., 801 mg,7.53 mmol) and stirred under a hydrogen atmosphere at rt overnight. Thereaction mixture was filtrated over Celite, washed with ethyl acetateand the filtrate concentrated in vacuo to give the title compound (1.76g, 79%) as racemic cis diastereomer which was not further purified.

UPLC-MS (ESI+): [M+H]⁺=333; R_(t)=1.52 min (Method F).

Reference Example 2-137 (±)5-bromo-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

The title compound was prepared in an analogous manner to referenceexample 2-51, starting from intermediate 1-2 and1-isothiocyanato-4-[(trifluoromethyl)sulfanyl]benzene (CAS No.[189281-95-6]).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.90-1.18 (m, 10H), 1.32-1.48 (m,2H), 1.68-1.80 (m, 1H), 1.80-1.93 (m, 2H), 2.01 (t, 1H), 4.68 (t, 1H),7.12-7.20 (m, 1H), 7.52-7.62 (m, 2H), 7.65 (d, 2H), 7.83 (d, 2H), 9.35(s, 1H).

UPLC-MS: R_(t)=1.81 min; m/z=512.10 (ES+, M+1).

Intermediate 1-34 (±) methyl3-(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate

Step 1: methyl 3-(4-fluoro-3-nitrophenyl)propanoate

A solution of 3-(4-fluoro-3-nitrophenyl)propanoic acid (commerciallyavailable, CAS No. [160877-40-7]; 5.00 g, 23.5 mmol) in methanol (40 mL)was cooled in an ice-bath and dropwise treated with concentratedsulfuric acid (3.50 eq., 8.05 g, 4.38 mL, 82.1 mmol). Upon addition themixture was warmed to rt and stirred at this temperature for 2 h. Thereaction mixture was diluted with ethyl acetate (300 mL) and the organiclayer washed with water (three times) and brine. The organic layer wasdried over sodium sulfate and concentrated in vacuo to give the titlecompound (5.2 g, 92%) which was not further purified.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.70 (t, 2H), 2.93 (t, 2H), 3.58 (s,3H), 7.51 (dd, 1H), 7.70 (ddd, 1H), 8.04 (dd, 1H).

UPLC-MS (ESI+): [M+MeCN+H]⁺=269; R_(t)=1.08 min (Method E).

Step 2: (±) methyl3-(3-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate

A solution of methyl 3-(4-fluoro-3-nitrophenyl)propanoate (700 mg, 3.08mmol) from step 1 in 1,4-dioxane (60 mL) was treated with3,3,5-trimethylcyclohexanamine (mixture of stereoisomers, commerciallyavailable; 1.20 eq., 522 mg, 3.70 mmol), sodium carbonate (2.00 eq., 852mg, 6.16 mmol) and cesium carbonate (1.00 eq., 1.00 g, 3.08 mmol),warmed to 90° C. and stirred at this temperature overnight. Upon coolingto rt the precipitate was filtered off and washed with ethyl acetate.The combined filtrates were concentrated in vacuo and the obtainedresidue partitioned between water and ethyl acetate. The phases wereseparated and the aqueous layer extracted with ethyl acetate. Thecombined organic layers were washed with water (twice) and brine, driedover magnesium sulfate and concentrated in vacuo to give the titlecompound (1.00 g, 93%) which was not further purified.

¹H-NMR (400 MHz, DMSO-d₆, major cis-isomer): δ [ppm]=0.75-0.86 (m, 2H),0.88 (d, 3H), 0.93 (s, 3H), 1.01 (s, 3H), 1.10 (t, 1H), 1.34-1.37 (m,1H), 1.68-1.83 (m, 2H), 1.99-2.02 (m, 1H), 2.58-2.62 (m, 2H), 2.75-2.79(m, 2H), 3.57 (s, 3H), 3.73-3.82 (m, 1H), 7.07 (d, 1H), 7.44 (dd, 1H),7.79 (br. d., 1H), 7.89 (d, 1H).

Step 3: (±) methyl3-(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate

A solution of (±) methyl3-(3-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate(1.00 g, 2.87 mmol) from step 2 in ethyl acetate (120 mL) was treatedwith Pd/C (10 wt %; 0.33 eq., 100 mg, 0.94 mmol) and stirred under ahydrogen atmosphere at rt overnight. The reaction mixture was filtratedover Celite, washed with ethyl acetate and the filtrate concentrated invacuo. The obtained material was purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the title compound (600 mg, 66%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.64 (q, 1H), 0.76 (t, 1H), 0.85-0.96(m, 10H), 1.32-1.37 (m, 1H), 1.65-1.69 (m, 2H), 1.94-1.98 (m, 1H),2.56-2.63 (m, 2H), 3.27-3.37 (m, 1H), 3.57 (s, 3H), 3.86 (br. d., 1H),4.42 (br. s., 2H), 6.28-6.37 (m, 3H).

UPLC-MS (ESI+): [M+H]⁺=319; R_(t)=1.50 min (Method F).

Intermediate 1-35 (±) methyl(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate

Step 1: (±) methyl(3-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate

2.5 g (12 mmol) methyl 2-(4-fluoro-3-nitrophenyl)acetate (CAS No.[226888-37-5]) were given in 133 mL tetrahydrofurane. After addition of1.8 g (9.6 mmol) potassium carbonate 2.3 g (16 mmol)3,3,5-trimethylcyclohexanamine (commercially available) were added andthe reaction mixture was heated at 50° C. for 48 h. The reaction mixturewas filtered and evaporated. The residue was partitioned between withethyl acetate and water. The aqueous phase was reextracted twice withethyl acetate and the combined organic extracts were dried (sodiumsulfate). The solvent was evaporated yielding 4.6 g (>100%) of thedesired product.

Step 2: (±) methyl(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate

4.6 g (14 mmol) (±) methyl(3-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate fromstep 1 were dissolved in ethyl acetate (207 mL). After addition of 186mg (2.6 mmol) Pd/C(10%) the reaction mixture was stirred under ahydrogen atmosphere overnight at room temperature. The catalyst wasfiltered off via a glass fibre filter and washed with ethyl acetate.After evaporation of the solvent 3 g (71%) of the desired product(crude) were obtained.

UPLC-MS (ESI+): [M+H]⁺=305; R_(t)=1.44 min (Method F).

Intermediate 1-36 methyl{3-amino-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate

Intermediate 1-36 was synthesized in analogy to intermediate 1-35 frommethyl 2-(4-fluoro-3-nitrophenyl)acetate (CAS No. [226888-37-5]) and3,3,5,5-tetramethylcyclohexanamine hydrochloride (commerciallyavailable).

UPLC-MS (ESI+): [M+H]⁺=319; R_(t)=1.49 min (Method F).

Intermediate 1-37 (±) methyl3-(3-amino-4-{[-3,3-dimethylcyclohexyl]amino}phenyl)propanoate

Intermediate 1-37 was synthesized in analogy to intermediate 1-34 frommethyl 3-(4-fluoro-3-nitrophenyl)propanoate (intermediate 1-34, step 1)and (±) 3,3-dimethylcyclo-hexanamine (commercially available)

UPLC-MS (ESI+): [M+H]⁺=305; R_(t)=1.41 min (Method F).

Intermediate 1-38 methyl3-{3-amino-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}propanoate

Intermediate 1-38 was synthesized in analogy to intermediate 1-34 frommethyl 3-(4-fluoro-3-nitrophenyl)propanoate (intermediate 1-34, step 1)and 3,3,5,5-tetramethylcyclohexanamine hydrochloride (commerciallyavailable) UPLC-MS (ESI+): [M+H]⁺=363; R_(t)=1.69 min (Method A).

Intermediate 1-39 (±) methyl(5-amino-2-methyl-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate

Step 1: (4-fluoro-2-methyl-5-nitrophenyl)acetic acid

(4-fluoro-2-methylphenyl)acetic acid (6 g, 35 mmol CAS No.[407640-40-8]) was suspended in conc. sulfuric acid (36 ml) and cooledto −10° C. Then a mixture of nitric acid (1.8 ml 90%) and sulfuric acid(2.6 ml conc.) was added dropwise, stirred at −10° C. for 1 h and pouredon ice. The precipitate was filtered off and dried to give 6.46 g (84%)of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.31 (s, 3H), 3.75 (s, 2H), 7.45 (d,1H), 8.05 (d, 1H).

Step 2: methyl (4-fluoro-2-methyl-5-nitrophenyl)acetate

A solution of (4-fluoro-2-methyl-5-nitrophenyl)acetic acid (9 g, 42mmol) from step 1 in methanol (78 mL) was cooled in an ice-bath anddropwise treated with concentrated sulfuric acid (3.50 eq., 7.8 mL, 147mmol). Upon addition the mixture was warmed to rt and stirred at thistemperature for 24 h. The reaction mixture was concentrated to the halfvolume in vacuo, diluted with ethyl acetate and the organic layer washedwith water, saturated sodium hydrogencarbonate solution and brine. Theorganic layer was dried over sodium sulfate and concentrated in vacuo togive the title compound (8.7 g 90%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.32 (s, 3H), 3.64 (s, 3H), 3.88 (s,2H), 7.48 (d, 1H), 8.09 (d, 1H).

Step 3: (±) methyl(2-methyl-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate

2 g (8.8 mmol) methyl (4-fluoro-2-methyl-5-nitrophenyl)acetate from step2 were given in 133 mL tetrahydrofurane. After addition of 1.33 g (9.6mmol) potassium carbonate the reaction mixture was stirred for 10 min atroom temperature. 1.6 g (11 mmol) 3,3,5-Trimethylcyclohexanamine(commercially available) were added and the reaction mixture was heatedat 50° C. overnight. The reaction mixture was filtered and the filtrateevaporated. The residue was partitioned between with ethyl acetate andwater. The aqueous phase was reextracted twice with ethyl acetate andthe combined organic extracts were dried (sodium sulfate). The solventwas evaporated yielding 3.32 g (>100%) of the desired product.

UPLC-MS (ESI+): [M+H]⁺=349; R_(t)=1.65 min (Method F).

Step 4: (±) methyl(5-amino-2-methyl-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate

3.3 g (9.5 mmol) (±) methyl(2-methyl-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetatefrom step 3 were dissolved in ethyl acetate (143 mL). After addition of198 mg (1.8 mmol) Pd/C the reaction mixture was stirred under a hydrogenatmosphere overnight at room temperature. The catalyst was filtered offvia a glass fibre filter and washed with ethyl acetate. Due toincomplete conversion the hydrogenation procedure was repeated twotimes. After evaporation of the solvent 3 g (98%) of the desired product(crude) were obtained.

UPLC-MS (ESI+): [M+H]⁺=318; R_(t)=1.50 min (Method F).

Intermediate 1-40 methyl{5-amino-2-methyl-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate

The title compound was prepared in analogy to intermediate 1-39 (step 3,4) from methyl (4-fluoro-2-methyl-5-nitrophenyl)acetate (intermediate1-39, product from step 2) and 3,3,5,5-tetramethylcyclohexanamine(commercially available).

UPLC-MS (ESI+): [M+H]⁺=333; R_(t)=1.54 min (Method F).

Intermediate 1-41 (±) methyl(5-amino-2-fluoro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)-acetate

Step 1: (2,4-difluoro-5-nitrophenyl)acetic acid

(2,4-Difluorophenyl)acetic acid (commercially available) (6 g, 34 mmol)was suspended in conc. sulfuric acid (36 mL) and cooled to 0° C. Then amixture of nitric acid (1.8 ml 90%) and sulfuric acid (2.5 mL conc.) wasadded dropwise, stirred at 0° C. for 1 h and poured on ice. Theprecipitate was filtered off and dried to give 6.9 g (91%) of the titlecompound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=2.77 (s, 2H), 7.65-7.77 (m, 1H), 8.32(tr, 1H)

12.71 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=232; R_(t)=1.03 min (Method E).

Step 2: methyl (2,4-difluoro-5-nitrophenyl)acetate

A solution of (2,4-difluoro-5-nitrophenyl)acetic acid (10 g, 46 mmol)from step 1 in methanol (85 mL) was cooled in an ice-bath and dropwisetreated with concentrated sulfuric acid (3.50 eq., 8.6 ml, 161 mmol).Upon addition the mixture was warmed to rt and stirred at thistemperature for 24 h. The reaction mixture was concentrated to the halfvolume in vacuo, diluted with ethyl acetate and the organic layer washedwith water, saturated sodium hydrogencarbonate solution and brine. Theorganic layer was dried over sodium sulfate and concentrated in vacuo togive the title compound (10.5 g 98%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=3.66 (s, 2H), 3.91/s, 3H), 7.69-7.80(m, 1H), 8.36 (tr, 1H).

Step 3: (±) methyl(2-fluoro-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)-acetate

Methyl (2,4-difluoro-5-nitrophenyl)acetate (3.5 g, 15 mmol) from step 2was dissolved in acetonitrile (130 mL). Triethylamine (4.6 mL, 33 mmol)and 3,3,5-trimethylcyclohexanamine hydrochloride (2.9 g, 16 mmol,commercially available) were added and the mixture was stirred at 50° C.overnight. The solvent was evaporated and the residue was partitionedbetween water and ethyl acetate and extracted with ethyl acetate. Thecombined organic layers were washed with water, brine, dried with sodiumsulfate and concentrated in vacuo to give the title compound (5.3 g,99%).

UPLC-MS (ESI+): [M+H]⁺=353; R_(t)=1.66 min (Method F).

Step 4: (±) methyl(5-amino-2-fluoro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)-acetate

(±) Methyl(2-fluoro-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate(3 g, 8.5 mmol) from step 3 was suspended in methanol (35 mL) andtin(II) chloride (11.3 g, 59 mmol) was added. The mixture was stirred at70° C. overnight and concentrated in vacuo. The residue was partitionedbetween water (200 mL) and ethylacetate (200 mL), then the pH wasadjusted to 10 with sodium carbonate solution. The mixture was filteredover celite and the organic layer was washed with water, brine, driedwith sodium sulfate and concentrated in vacuo to give 2.46 g (89%) ofthe desired product.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.61-0.71 (m, 1H), 0.78 (tr, 1H),0.85-1.02 (m, 10H), 1.32-1.40 (m, 1H), 1.62-1.79 (m, 2H), 1.93-2.02 (m,1H), 3.41 (s, 2H), 3.59 (s, 3H), 4.27-4.44 (m, 2H), 6.22 (d, 1H), 6.39(d, 1H).

Intermediate 1-42 methyl{5-amino-2-fluoro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate

The title compound was prepared in analogy to the preparation ofintermediate 1-41, 3,3,5,5-tetramethylcyclohexanamine (commerciallyavailable) was used in step 2 instead of 3,3,5-trimethylcyclohexanaminehydrochloride.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.87-1.00 (m, 9H), 1.09 (s, 6H),1.22-1.30 (m, 1H), 1.68-1.77 (m, 2H), 3.41 (s, 2H), 3.58 (s, 3H),4.28-4.44 (m, 2H), 6.18 (d, 1H), 6.39 (d, 1H).

Intermediate 1-43 (±) methyl(5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)-acetate

Step 1: (±) methyl(2-methoxy-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)-acetate

(±) Methyl(2-fluoro-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate(2.5 g, 7 mmol, product from step 2 of intermediate 1-41) was suspendedin methanol (50 mL) and treated with sodium methylate in methanol (13.3mL, 70 mmol, 30% solution) overnight at rt. Then the mixture waspartitioned between water and ethyl acetate, the layers separated andthe aqueous layer extracted with ethyl acetate. The combined organiclayers were washed with water, brine, dried with sodium sulfate andconcentrated in vacuo to give the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.80-0.97 (m, 12H), 1.34-1.41 (m,1H), 1.74-1.85 (m, 2H), 2.00-2.08 (m, 1H), 3.55 (s, 2H), 3.59 (s, 3H),3.88 (s, 3H), 6.35 (s, 1H), 7.98 (s, 1H), 8.21 (d, 1H).

UPLC-MS (ESI+): [M+H]⁺=365; R_(t)=1.61 min (Method F).

Step 2: (±) methyl(5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate

A solution of (±) methyl(2-methoxy-5-nitro-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)acetate(2.66 g, 7.3 mmol) from step 1 in tetrahydrofurane (70 mL) and methanol(30 mL) was treated with Pd/C (10 wt %; 0.33 eq., 250 mg, 2.8 mmol) andstirred under a hydrogen atmosphere at rt for 6 h. The reaction mixturewas filtrated over Celite, washed with ethyl acetate and the filtrateconcentrated in vacuo to give the title compound (2.38 g, 97%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.65-0.82 (m, 2H), 0.85-1.03 (m,10H), 1.32-1.40 (m, 1H), 1.68-1.79 (m, 2H), 1.93-2.00 (m, 1H), 3.35 (s,2H), 3.55 (s, 3H), 3.62 (s, 3H), 3.97-4.13 (m, 2H), 6.14 (s, 1H), 6.36(s, 1H).

UPLC-MS (ESI+): [M+H]⁺=335; R_(t)=1.18 min (Method E).

Intermediate 1-44 methyl{5-amino-2-methoxy-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate

Step 1: methyl{2-methoxy-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate

Methyl{2-fluoro-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate(2.5 g 6.8 mmol, intermediate 1-42, product from step 3) was suspendedin methanol (50 mL) and treated with sodium methylate in methanol (13mL, 68 mmol, 30% solution) overnight at rt. Then the mixture waspartitioned between water and ethyl acetate, the layers separated andthe aqueous layer extracted with ethyl acetate. The combined organiclayers were washed with water, brine, dried with sodium sulfate andconcentrated in vacuo to give the title compound.

UPLC-MS (ESI+): [M+H]⁺=379; R_(t)=1.65 min (Method F).

Step 2: methyl{5-amino-2-methoxy-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate

Methyl{2-methoxy-5-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acetate(2.3 g, 6 mmol) from step 1 was suspended in methanol (30 mL) andtin(II) chloride (8 g, 42 mmol) was added. The mixture was stirred at70° C. overnight and evaporated. The residue was partitioned betweenwater (250 mL) and ethylacetate (200 mL), then the pH was adjusted to 10with sodium carbonate solution. The mixture was filtered over celite andthe organic layer was washed with water, brine, dried with sodiumsulfate, concentrated in vacuo and purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the title compound (1.09 g, 51%).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.91 (s, 6H), 1.10 (s, 6H), 1.23-1.30(m, 1H), 1.73-1.80 (m, 2H), 3.35 (s, 2H), 3.56 (s, 3H), 3.62 (s, 3H),4.03-4.12 (m, 2H), 6.15 (s, 1H), 6.37 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=348; R_(t)=1.42 min (Method D).

Intermediate 1-45 methyl 3-{3-amino-2-fluoro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}propanoate

Step 1: methyl(2E)-3-{2-fluoro-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}acrylate

4-Bromo-3-fluoro-2-nitro-N-(3,3,5,5-tetramethylcyclohexyl)aniline(prepared in step 1 of intermediate 1-27; 2.20 g, 5.89 mmol) wasdissolved in N,N-dimethylformamide (73 mL) followed by addition ofmethyl acrylate (1.59 mL, 17.68 mmol) and triethylamine (1.64 mL, 11.79mmol). The mixture was degassed with argon for 15 min thentetrakis(triphenylphosphine)palladium (681 mg, 0.59 mmol) was added andthe reaction was heated at 120° C. for 18 h. The reaction was cooled andbrine (50 mL) and ethyl acetate (50 mL) were added. The layers wereseparated and the aqueous layer was extracted with ethyl acetate (3×50mL). The combined organic layers were dried over solid sodium sulfateand concentrated under vacuum. The crude material was purified by flashchromatography (SiO₂-heptane/ethyl acetate) to give the title compound(0.88 mg, 39%) as an orange solid.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.96 (s, 6H), 1.09 (s, 6H), 1.05-1.31(m, 2H), 1.81 (d, 2H), 3.73 (m, 1H), 3.79 (s, 3H), 6.31 (d, 1H), 6.63(d, 1H), 7.52 (dd, 1H), 7.73 (d, 1H).

UPLC-MS (ESI−): [M−H]⁻=377; R_(t)=1.12 min (Method G).

Step 2: methyl3-{3-amino-2-fluoro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}propanoate

To a solution of methyl(2E)-3-{2-fluoro-3-nitro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}prop-2-enoate(880 mg, 2.32 mmol) from step 1 in tetrahydrofuran (44 mL) was added 5%palladium on carbon (494 mg, 0.23 mmol) and the reaction was stirredunder a hydrogen atmosphere (1 atm) for 18 h. The reaction was filteredthrough celite using ethyl acetate and the filtrate concentrated. Theresidue was purified by flash chromatography (SiO₂-heptane/ethylacetate) to give the title compound (858 mg, quantitative) as a brownoil.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.92 (s, 6H), 1.10 (s, 6H), 0.87-1.26(m, 4H), 1.85 (d, 2H), 2.58 (t, 2H), 2.87 (t, 2H), 3.20 (br. s., 3H),3.49-3.60 (m, 1H), 3.67 (s, 3H), 6.36 (d, 1H), 6.58 (dd, 1H).

UPLC-MS (ESI+): [M+H]⁺=351; R_(t)=1.05 min (Method G).

EXAMPLES Reference Example 2-1 (±)N-(2,4-diethylphenyl)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

250 mg (1.08 mmol) (+)N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine (intermediate1-5) was dissolved in 10 mL tetrahydrofurane. 206 mg (0.11 mmol)2,4-Diethyl-1-isothiocyanatobenzene and 337 μL (2.15 mmol)N,N′-diisopropylcarbodiimide were added and the reaction mixture wasstirred at 70° C. for 24 hours. The solvent was removed and the residuediluted with dichloromethane. The organic phase was washed with waterand brine. After drying over sodium sulfate the solvent was removed andthe residue was purified by column chromatography (hexane/ethyl acetate)yielding 264 mg (56%) of the desired product.

UPLC-MS: R_(t)=1.22 min.

MS (ESIpos): m/z=390.5 (M+H)⁺.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.74 (s, 3H), 0.88-1.01 (m, 7H),1.17-1.46 (m, 8H), 1.48-1.75 (m, 3H), 1.80-2.00 (m, 2H), 2.52-2.77 (m,4H), 4.09-4.35 (m, 1H), 5.99 (br. s., 1H), 6.92-7.26 (m, 5H), 7.37 (d,1H), 7.57 (d, 1H).

Reference Example 2-1-1N-(2,4-diethylphenyl)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine,enantiomer A

The racemic compound (±)N-(2,4-diethylphenyl)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-1; 78 mg) was separated via chiral HPLC (column:Chiralpak IA, 5 μM 250×20 mm; injection: 78 mg in 3×0.3 mL(acetone/ethyl acetate); solvent: carbon dioxide, 2-propanol,diethylamine (75:25:0.4); flow: 80 mL/min; detection: UV 254 nm) intoits enantiomers yielding 30 mg of the title compound (enantiomer A,retention time range: 2-5-4.0 min) and 30 mg of enantiomer B, describedin reference example 2-1-2.

Reference Example 2-1-2N-(2,4-diethylphenyl)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine,enantiomer B

The racemic compound (±)N-(2,4-diethylphenyl)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-1; 78 mg) was separated via chiral HPLC (column:Chiralpak IA, 5 μM 250×20 mm; injection: 78 mg in 3×0.3 mL(acetone/ethyl acetate); solvent: carbon dioxide, 2-propanol,diethylamine (75:25:0.4); flow: 80 mL/min; detection: UV 254 nm) intoits enantiomers yielding 30 mg of the title compound (enantiomer B,retention time range: 4.5-5.5 min) and 30 mg of enantiomer A, describedin reference example 2-1-1.

Example 2-8tert-butyl{[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]-amino}-1H-benzimidazol-5-yl]oxy}acetate

The compound was prepared in analogy to reference example 2-1 startingfrom 2.5 g (18.7 mmol) of intermediate 1-14 yielding 2.5 g (65%) of thedesired product.

LC-MS: R_(t)=1.72 min; MS (ES+, M+1) 562; MS (ES−, M−1) 560.

Example 2-9{[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]oxy}aceticacid

To a solution oftert-butyl{[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]oxy}acetate(example 2-8; 2.5 g, 4.45 mmol) in dioxane (20 mL) was added a solutionof HCl in dioxane (4N, 23 mL). The reaction mixture was then stirred for4 h at ambient temperature. Dioxane was then evaporated. The residue wassuspended in ethyl acetate, the precipitate was filtered off andsubsequently dried. The desired product was obtained in 71% yield (1.65g).

¹H-NMR (300 MHz, DMSO-d₆) δ [ppm]=0.99 (s, 6H), 1.14 (s, 6H), 1.21-1.42(m, 2H), 1.66-1.73 (m, 2H), 2.04 (t, 2H), 4.71 (s, 2H), 4.76 (br. m,1H), 6.85-6.91 (m, 2H), 7.48-7.54 (m, 2H), 7.61-7.65 (m, 2H), 7.70-7.82(m, 1H), 10.8 (br. s., 1H), 13.0 (br. s., 1H).

LC-MS: R_(t)=1.22 min; MS (ES+, M+1) 506; MS (ES−, M−1) 504.

Reference Example 2-24 (±) methyl2-{[4-(difluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazole-5-carboxylate

A solution of (±) methyl2-chloro-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazole-5-carboxylate(intermediate 1-21; 250 mg, 0.747 mmol) and 4-(difluoromethoxy)aniline(3.0 eq., 0.28 mL, 2.2 mmol) in NMP (0.5 mL) was heated to 110° C.overnight. The reaction mixture was diluted with dichloromethane andwashed with saturated aqueous sodium carbonate, water and brine. Theorganic layer was dried with sodium sulfate, concentrated in vacuo andthe obtained material was purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the title compound (231 mg, 67%).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.97-0.99 (m, 6H), 1.06-1.14 (m, 4H),1.39-1.46 (m, 2H), 1.72-1.81 (m, 1H), 1.87-1.90 (m, 2H), 2.06 (t, 1H),3.84 (s, 3H), 4.65-4.73 (m, 1H), 7.14 (t, 1H), 7.16-7.18 (m, 2H),7.63-7.68 (m, 2H), 7.76-7.78 (m, 2H), 7.91 (s, 1H), 9.05 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=458; R_(t)=1.38 min.

Reference Example 2-26 (±)2-{[4-(difluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazole-5-carboxylicacid

A solution of (±) methyl2-{[4-(difluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazole-5-carboxylate(reference example 2-24; 40 mg, 0.088 mmol) in a mixture of THF/water(1:1, 2 mL) was treated with lithium hydroxide (5.0 eq., 10 mg, 0.44mmol) and stirred at 70° C. for 20 h, cooled to rt and stirring at rtcontinued for 2 days. The reaction mixture was acidified with 2 Maqueous hydrochloric acid (pH 4-5) and extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried with sodium sulfateand concentrated in vacuo.

The obtained crude product (40 mg, 93%) was not further purified.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97-0.99 (m, 6H), 1.06-1.14 (m, 4H),1.39-1.46 (m, 2H), 1.73-1.82 (m, 1H), 1.87-1.90 (m, 2H), 2.06 (t, 1H),4.65-4.73 (m, 1H), 7.14 (t, 1H), 7.16-7.19 (m, 2H), 7.61-7.68 (m, 2H),7.75-7.78 (m, 2H), 7.89 (s, 1H), 9.05 (br. s., 1H), 12.48 (br. s., 1H).

UPLC-MS (ESI+): [M+H]⁺=444; R_(t)=1.19 min.

Reference Example 2-51 (±)N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine

0.71 g (0.72 mmol) (+)N¹-[(cis)-3,3,5-trimethylcyclohexyl]benzene-1,2-diamine (intermediate1-5) were dissolved in 14 mL tetrahydrofurane. 0.16 g (0.72 mmol)Trifluoromethoxyphenylisothiocyanate and 0.18 g (1.44 mmol)N,N′-diisopropylcarbodiimide were added, and the reaction mixture wasstirred at 70° C. for two hours.

The solvent was removed and the residue diluted with dichloromethane.The organic phase was washed with water and brine. After drying oversodium sulfate the solvent was removed and the residue was purified bycolumn chromatography (HPLC) yielding 0.13 g (41%) of the desiredproduct.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.89-1.00 (m, 6H), 1.00-1.13 (m, 4H),1.30-1.47 (m, 2H), 1.69-1.95 (m, 3H), 2.06 (t, 1H), 4.54-4.78 (m, 1H),6.92-7.11 (m, 2H), 7.24-7.44 (m, 3H), 7.53 (d, 1H), 7.80 (d, 2H), 9.02(s, 1H).

Reference Example 2-51-1N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine,enantiomer A

The racemic compound (±)N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-51; 120 mg) was separated via chiral HPLC (system:Agilent Prep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA,5 μM 250×20 mm; injection: 120 mg in 6×0.3 mL (dichloromethane);solvent: hexane, 2-propanol, diethylamine (70:30:0.1); flow: 20 mL/min;detection: UV 254 nm) into its enantiomers yielding 50 mg of the titlecompound (enantiomer A, retention time range: 4.8-5.5 min) and 38 mg ofenantiomer B, described in reference example 2-51-2.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.85-1.01 (m, 6H), 1.01-1.24 (m, 4H),1.32-1.44 (m, 2H), 1.72-1.94 (m, 3H), 2.06 (t, 1H), 4.60-4.69 (m, 1H),7.00-7.04 (m, 2H), 7.30 (d, 2H), 7.35-7.40 (m, 1H), 7.53 (d, 1H),7.77-7.82 (m, 2H), 8.99 (s, 1H).

Reference Example 2-51-2N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine,enantiomer B

The racemic compound (±)N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-51; 120 mg) was separated via chiral HPLC (system:Agilent Prep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA,5 μM 250×20 mm; injection: 120 mg in 6×0.3 mL (dichloromethane);solvent: hexane, 2-propanol, diethylamine (70:30:0.1); flow: 20 mL/min;detection: UV 254 nm) into its enantiomers yielding 38 mg of the titlecompound (enantiomer B, retention time range: 5.9-6.9 min) and 50 mg ofenantiomer A, described in reference example 2-51-1.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.94-1.00 (m, 6H), 1.02-1.14 (m, 4H),1.32-1.44 (m, 2H), 1.73-1.93 (m, 3H), 2.06 (t, 1H), 4.60-4.69 (m, 1H),6.98-7.06 (m, 2H), 7.28-7.39 (m, 3H), 7.51-7.56 (m, 1H), 7.77-7.82 (m,2H), 8.99 (s, 1H).

The reference examples in Table 2 were prepared in an analogous mannerto reference example 2-51, starting from the corresponding intermediatesand where appropriate separated into their enantiomers as described.

TABLE 2 Reference Example, (Inter- Method/ mediate) Structure/NameAnalytical data 2-61, (1-2)

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 0.91-1.21 (m, 10H), 1.32-1.50 (m,2H), 1.65-2.09, m, 4H), 4.58-4.73 (m, 1H), 7.08-7.18 (m, 1H), 7.27-7.38(m, 2H), 7.46-7.58 (m, 2H), 7.75-7.86 (m, 2H), 9.12 (s, 1H). UPLC-MS:R_(t) = 1.69 min; m/z = 496.1 (ES+, M + 1). and

(±) 5-bromo-N-[4- (trifluoromethoxy)phenyl]-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-2-amine 2-61-1 5-bromo-N-[4-System: Agilent Prep 1200, 2xPrep (trifluoromethoxy)phenyl]-1- Pump,DLA, MWD, Pre FC; column: [(cis)-3,3,5- Chiralpak IA, 5 μM 250 × 20 mm;injection: trimethylcyclohexyl]-1H- 257 mg in 13 × 0.4 mLdichloromethane; benzimidazol-2-amine, solvent: hexane/2-propanol/enantiomer A diethylamine (70:30:0.1); flow: 25 mL/ min; detection: UV254 nm; R₁ = 3.6- 4.6 min. ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] =0.87-1.16 (m, 10H), 1.27-1.50 (m, 2H), 1.61-2.00 (m, 4H), 4.53-4.77 (m,1H), 7.13 (dd, 1H), 7.32 (d, 2H), 7.44- 7.58 (m, 2H), 7.74-7.86 (m, 2H),9.14 (s, 1H). 2-61-2 5-bromo-N-[4- System: Agilent Prep 1200, 2xPrep(trifluoromethoxy)phenyl]-1- Pump, DLA, MWD, Prep FC; column:[(cis)-3,3,5- Chiralpak IA, 5 μM 250 × 20 mm; injection:trimethylcyclohexyl]-1H- 257 mg in 13 × 0.4 mL dichloromethane;benzimidazol-2-amine, solvent: hexane/2-propanol/ enantiomer Bdiethylamine (70:30:0.1); flow: 25 mL/ min; detection: UV 254 nm; R₁ =5.0- 6.2 min. ¹H-NMR ¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 0.88-1.18 (m,10H), 1.31-1.49 (m, 2H), 1.64-1.91 (m, 3H), 2.00 (t, 1H), 4.65 (t, 1H),7.13 (dd, 1H), 7.32 (d, 2H), 7.45-7.57 (m, 2H), 7.73-7.86 (m, 2H), 9.14(s, 1H). 2-62, (1-2)

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]= 0.82-1.19 (m, 10H), 1.31-1.50 (m,2H), 1.63-2.09 (m, 4H), 4.68 (t, 1H), 7.09-7.19 (m, 1H), 7.52-7.62 (m,2H), 7.68 (d, 2H), 7.90 (d, 2H), 9.38 (s, 1H). UPLC-MS: R_(t) = 1.77min; m/z = 480.1 (ES+, M + 1).. and

(±) 5-bromo-N-[4- (trifluoromethyl)phenyl]-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-2-amine

Example 2-110 (±) methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)acrylate

548 mg (1.10 mmol) (±)5-Bromo-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-61), 190.1 mg (2.21 mmol) methacrylate, 57.1 mg(0.19 mmol) tri-2-tolylphosphine and 24.8 mg (0.11 mmol) palladium(II)acetate were dissolved in 7.8 mL acetonitrile. After addition of 0.18 mL(1.26 mmol) triethylamine the reaction mixture was heated in themicrowave oven at 110° C. for 60 min. The reaction mixture was given ona flash column and was washed with ethyl acetate (250 mL) to remove thecatalyst and the salts. The filtrate was evaporated to dryness and theresidue was purified by column chromatography to yield 328.5 mg (56%) ofthe title compound.

UPLC-MS: R_(t)=1.57 min; m/z=502 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.23 (m, 10H), 1.31-1.48 (m,2H), 1.68-2.12 (m, 4H), 3.69 (s, 3H), 4.57-4.77 (m, 1H), 6.55 (d, 1H),7.28-7.43 (m, 3H), 7.59 (d, 1H), 7.70-7.81 (m, 2H), 7.85 (d, 2H), 9.14(s, 1H).

Example 2-110-1 methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)acrylate,enantiomer A

The racemic compound (±) methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate(example 2-110; 328 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM250×30 mm; injection: 328 mg in 7×0.57 mL dichloromethane; solvent:hexane, ethanol, diethylamine (80:20:0.1); flow: 50 mL/min; detection:UV 280 nm) into its enantiomers yielding 115 mg of the title compound(enantiomer A, retention time range: 10-12.8 min) and 120 mg ofenantiomer B, described in example 2-110-2.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.23 (m, 10H), 1.40 (t, 2H),1.68-1.98 (m, 3H), 2.03 (t, 1H), 3.71 (s, 3H), 4.58-4.78 (m, 1H), 6.55(d, 1H), 7.28-7.43 (m, 3H), 7.59 (d, 1H), 7.68-7.81 (m, 2H), 7.85 (d,2H), 9.14 (s, 1H).

Example 2-110-2 methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)acrylate,enantiomer B

The racemic compound (±) methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate(example 2-110; 328 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM250×30 mm; injection: 328 mg in 7×0.57 mL dichloromethane; solvent:hexane, ethanol, diethylamine (80:20:0.1); flow: 50 mL/min; detection:UV 280 nm) into its enantiomers yielding 120 mg of the title compound(enantiomer B, retention time range: 13-15.9 min) and 115 mg ofenantiomer A, described in example 2-110-1.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.23 (m, 10H), 1.40 (t, 2H),1.68-1.98 (m, 3H), 2.03 (t, 1H), 3.71 (s, 3H), 4.58-4.78 (m, 1H), 6.55(d, 1H), 7.28-7.43 (m, 3H), 7.59 (d, 1H), 7.68-7.81 (m, 2H), 7.85 (d,2H), 9.14 (s, 1H).

Example 2-111 (±)(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylicacid

70 mg (0.14 mmol) (±) Methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate(example 2-110) were dissolved in 0.6 mL dioxane. 6.7 mg (0.28 mml) LiOHand 0.2 mL H₂O were added and the reaction mixture was stirred at 70° C.for 2.5 hours. The reaction mixture was evaporated to dryness and theresidue was suspended in water (10 mL). After acidification of themixture to pH 4 (1N HCl) the reaction mixture was stirred for two hoursat room temperature. The solid was filtered off, washed with water anddried overnight yielding 49.3 mg (69%) of the title compound.

UPLC-MS: R_(t)=1.35 min; m/z=488.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.21 (m, 10H), 1.31-1.52 (m,2H), 1.68-2.13 (m, 4H), 4.69 (br., 1H), 6.43 (d, 1H), 7.19-7.48 (m, 3H),7.52-7.73 (m, 3H), 7.81 (d, 2H), 9.39 (br. s, 1H), 12.18 (br. s., 1H).

Example 2-111-1(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylicacid, enantiomer A

115 mg (0.23 mmol) Methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate,enantiomer A (example 2-110-1) were saponified as described in theaforementioned example 2-111 yielding 83.2 mg (71%) of the desiredcompound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.88-1.18 (m, 10H), 1.34-1.50 (m,2H), 1.67-1.84 (m, 1H), 1.88 (d, 2H), 2.04 (t, 1H), 4.68 (br. s., 1H),6.43 (d, 1H), 7.29-7.44 (m, 3H), 7.53-7.74 (m, 3H), 7.81 (d, 2H), 9.29(br. s., 1H), 12.19 (br. s., 1H).

Example 2-111-2(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylicacid, enantiomer B

120 mg (0.24 mmol) Methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate,enantiomer B (example 2-110-2) were saponified as described in example2-111 yielding 90.4 mg (74%) of the desired compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.88-1.18 (m, 10H), 1.32-1.57 (m,2H), 1.67-1.98 (m, 3H), 2.04 (t, 1H), 4.71 (br. s., 1H), 6.43 (d, 1H),7.30-7.51 (m, 3H), 7.55-7.74 (m, 3H), 7.78 (d, 2H), 9.58 (br. s., 1H),12.19 (br. s., 1H).

Example 2-112 (−) methyl(2E)-3-{2-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}acrylate

500 mg (0.98 mmol) (±)5-Bromo-N-{4-[(trifluoromethyl)sulfanyl]phenyl}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-137), 168 mg (1.95 mmol) methacrylate, 50.5 mg(0.17 mmol) tri-2-tolylphosphine and 21.9 mg (0.1 mmol) palladium(II)acetate were dissolved in 6.9 mL acetonitrile. After addition of 0.16 mL(1.11 mmol) triethylamine the reaction mixture was heated in themicrowave oven at 110° C. for 60 min. Due to an incomplete reactionadditional reagents were added (1 eq. each) and heating was continued ina heating block overnight (110° C.). The reaction mixture was given on aflash column and washed with ethyl acetate (250 mL) to remove thecatalyst and the salts. The filtrate was evaporated to dryness and theresidue was purified by column chromatography yielding 38.5 mg (7%) ofthe title compound.

UPLC-MS: R_(t)=1.69 and 1.75 min; m/z=518.2 (ES+, M+1, Method B).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.91-1.18 (m, 10H), 1.32-1.49 (m,2H), 1.70-1.98 (m, 3H), 2.04 (t, 1H), 3.71 (s, 3H), 4.70 (br., 1H), 6.58(d, 1H), 7.38-7.48 (m, 1H), 7.54-7.90 (m, 7H), 9.35 (s, 1H).

Example 2-113 (±)(2E)-3-{2-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}acrylicacid

30 mg (0.06 mmol) (±) Methyl(2E)-3-{2-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}acrylate(example 2-112) were dissolved in 0.3 mL dioxane. 2.8 mg (0.12 mml) LiOHand 0.08 mL H₂O were added and the reaction mixture was stirred at 70°C. for 2.5 hours. The reaction mixture was evaporated to dryness and theresidue was suspended in water (10 mL). After acidification of themixture to pH 4 (1N HCl) the reaction mixture was stirred for two hoursat room temperature. The solid was filtered off, washed with water anddried overnight yielding 21.5 mg (70%) of the title compound.

UPLC-MS: R_(t)=1.51 min; m/z=504.2 (ES+, M+1).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.90-1.17 (m, 10H), 1.39 (d, 1H),1.47 (d, 1H), 1.67-1.85 (m, 1H), 1.89 (br., 2H), 2.04 (t, 1H), 4.71 (t,1H), 6.46 (d, 1H), 7.45 (d, 1H), 7.59-7.89 (m, 7H), 9.69 (br., 1H),12.23 (br., 1H).

Example 2-114 (±) methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoate

1.01 g (2.01 mmol) (±) Methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate(example 2-110) were dissolved in 43.9 mL ethanol. 42.9 mg (0.4 mmol)Pd/C were added and the reaction mixture was stirred under an H₂atmosphere at room temperature for 12 hours. The catalyst was filteredoff via a glass fibre filter, the solvent was evaporated and the residuepurified by column chromatography yielding 0.63 g (56%) of the desiredcompound.

UPLC-MS: R_(t)=1.31 min; m/z=504.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-de): 8 [ppm]=0.88-1.13 (m, 10H), 1.38 (d, 2H),1.70-1.92 (m, 3H), 1.95-2.09 (m, 1H), 2.63 (t, 2H), 2.88 (t, 2H), 3.57(s, 3H), 4.61 (br. s., 1H), 6.87 (d, 1H), 7.21 (s, 1H), 7.30 (d, 2H),7.42 (d, 1H), 7.78 (d, 2H), 8.98 (s, 1H).

Example 2-114-1 methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A

The racemic compound (±) methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate(example 2-114; 627 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM250×20 mm; injection: 627 mg in 8×0.7 mL dichloromethane/methanol;solvent: hexane, 2-propanol, diethylamine (70:30:0.1); flow: 40 mL/min;detection: UV 254 nm) into its enantiomers yielding 214 mg of the titlecompound (enantiomer A, retention time range: 7.8-8.9 min) and 200 mg ofenantiomer B, described in example 2-114-2. The title compound(enantiomer A) was further characterized by analytical chiral HPLC(System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: ChiralpakIA 3 μm 100×4.6 mm; Solvent hexane/2-propanol/diethylamine 70:30:0.1(v/v/v); Flow: 1.0 mL/min; Temperature: 25° C.; Solution: 1.0 mg/mLEtOH/MeOH (1:1); Injection: 5.0 μl; Detection: DAD 254 nm): R_(t)=3.64min.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.88-1.15 (m, 10H), 1.38 (d, 2H),1.68-1.94 (m, 3H), 2.02 (t, 1H), 2.56-2.68 (m, 2H), 2.80-2.94 (m, 2H),3.57 (s, 3H), 4.51-4.71 (m, 1H), 6.87 (d, 1H), 7.22 (s, 1H), 7.30 (d,2H), 7.42 (d, 1H), 7.78 (d, 2H), 8.98 (s, 1H).

Another batch of methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A was additionally characterized by specific opticalrotation: [α]_(D) ²⁰=13.2°+/−0.06° (C=1.0000 g/100 mL, methanol).

Example 2-114-2 methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B

The racemic compound (±) methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate(example 2-114; 627 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM250×20 mm; injection: 627 mg in 8×0.7 mL dichloromethane/methanol;solvent: hexane, 2-propanol, diethylamine (70:30:0.1); flow: 40 mL/min;detection: UV 254 nm) into its enantiomers yielding 200 mg of the titlecompound (enantiomer B, retention time range: 12.7-14.8 min) and 214 mgof enantiomer A, described in example 2-114-1. The title compound(enantiomer B) was further characterized by analytical chiral HPLC(System: Waters: Alliance 2695, DAD 996, ESA: Corona; Column: ChiralpakIA 3 μm 100×4.6 mm; Solvent hexane/2-propanol/diethylamine 70:30:0.1(v/v/v); Flow: 1.0 mL/min; Temperature: 25° C.; Solution: 1.0 mg/mLEtOH/MeOH (1:1); Injection: 5.0 μl; Detection: DAD 254 nm): R_(t)=5.74min.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.13 (m, 10H), 1.38 (d, 2H),1.65-1.91 (m, 3H), 2.02 (t, 1H), 2.63 (t, 2H), 2.87 (t, 2H), 3.57 (s,3H), 4.61 (br. s., 1H), 6.82-6.91 (m, 1H), 7.22 (s, 1H), 7.30 (d, 2H),7.42 (d, 1H), 7.78 (d, 2H), 8.99 (s, 1H).

Another batch of methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B was additionally characterized by specific opticalrotation: [α]_(D) ²⁰=−12.2°+/−0.04° (C=1.0000 g/100 mL, methanol).

Example 2-115 (±) methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate

Starting from 150 mg (0.31 mmol) (±) methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]-amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate(example 2-138) the title compound was prepared in analogy to example2-114. 136.4 mg (86%) were obtained.

UPLC-MS: R_(t)=1.41 min; m/z=488.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.07 (m, 10H), 1.39 (d, 2H),1.70-1.92 (m, 3H), 2.03 (t, 1H), 2.64 (t, 2H), 2.89 (t, 2H), 3.58 (s,3H), 4.55-4.73 (m, 1H), 6.87-6.95 (m, 1H), 7.27 (s, 1H), 7.46 (d, 1H),7.60-7.69 (m, 2H), 7.82-7.91 (m, 2H), 9.24 (s, 1H).

The enantiomers of the racemic material of example 2-115 were separatedby chiral preparative HPLC (System: 2× Labomatic Pump HD-3000, LabomaticAS-3000, Knauer DAD 2600, Labomatic Labcol Vario 4000 Plus; Column:Chiralpak IF 5 μm 250×30 mm; Solvent: hexane/2-propanol/diethylamine70:30:0.1 (v/v/v); Flow: 50 mL/min; Temperature: rt; Solution: 520 mg/5mL DCM/2-propanol; Injection: 4×1.3 mL; Detection: UV 254 nm) andanalytically characterized by chiral HPLC (System: Agilent 1260; Column:Chiralpak IF 5 μm 150×4.6 mm; Solvent: hexane/2-propanol/diethylamine70:30:0.1 (v/v/v); Flow: 1.0 mL/min; Temperature: 25° C.; Solution: 1.0mg/mL EtOH/MeOH 2:1; Injection: 5.0 μl; Detection: DAD 254 nm) andspecific optical rotation:

Example 2-115-1 methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A

R_(t)=3.04 min; [α]_(D) ²⁰=10.5°+/−0.99° (C=1.0000 g/100 mL, methanol).

Example 2-115-2 methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate, enantiomer B

R_(t)=4.34 min; [α]_(D) ²⁰=−13.3°+/−0.80° (C=1.0000 g/100 mL, methanol).

The examples in Table 3 were prepared in an analogous manner toreference example 2-150, starting from (±) methyl3-(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate(intermediate 1-34) and the corresponding commercially availablethioisocyanates. The enantiomers were separated and analyzed accordingto the given procedures.

TABLE 3 Example/ Name of isothiocya- nate used Structure/Name Analyticaldata 2-172 1- isothiocya- nato-4- (propan- 2- yloxy)ben- zene

 

  (±) methyl 3-(2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.95-0.97 (m, 6H), 1.03- 1.10 (m, 4H), 1.25 (d, 6H),1.37- 1.40 (m, 2H), 1.68-1.88 (m, 3H), 2.03 (t, 1H), 2.60-2.64 (m, 2H),2.85-2.89 (m, 2H), 3.58 (s, 3H), 4.47-4.62 (m, 2H), 6.81 (dd, 1H),6.86-6.90 (m, 2H), 7.15 (d, 1H), 7.35 (d, 1H), 7.54-7.58 (m, 2H), 8.53(br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 478; R_(t) = 1.64 min (MethodF). 2-172-1 methyl 3-(2-{[4-(propan-2- Separation:yloxy)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep 1200,trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)propanoate, FC; Column: Chiralpak IA 5 μm enantiomer A250 × 20 mm; Solvent: hexane/2- propanol 72:28 (v/v) + 0.1%diethylamine; Flow: 10 mL/min; Temperature: rt; Solution: 128 mg/ 1.5 mLDCM/MeOH 1:1; Injection: 8 × 0.2 mL; Detection: UV 254 nm; Analysis:System: Agilent 1260/Agilent 1290; Column: Chiralpak IA 3 μm 100 × 4.6mm; Solvent: hexane/2- propanol 69:31; Flow: 1.0 mL/min; Temperature:25° C.; Solution: 1.0 mg/mL EtOH/MeOH 1:1; Injection: 5.0 μl; Detection:DAD 254 nm: R_(t) = 4.14 min. 2-172-2 methyl 3-(2-{[4-(propan-2- R_(t) =6.27 min. yloxy)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate, enantiomer B 2-173 1- isothiocya- nato-4-(propan- 2- yl)benzene

 

  (±) methyl 3-(2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.95-0.97 (m, 6H), 1.03- 1.09 (m, 4H), 1.20 (d, 6H),1.37- 1.40 (m, 2H), 1.69-1.91 (m, 3H), 2.02 (t, 1H), 2.61-2.65 (m, 2H),2.79-2.90 (m, 3H), 3.59 (s, 3H), 4.57-4.63 (m, 1H), 6.84 (dd, 1H),7.15-7.18(m, 3H), 7.38 (d, 1H), 7.55-7.58 (m, 2H), 8.64 (br. s., 1H).UPLC-MS (ESI+): [M + H]⁺ = 462; R_(t) = 1.72 min (Method F). 2-173-1methyl 3-(2-{[4-(propan-2- Separation: yl)phenyl]amino}-1-[(cis)-3,3,5-System: Agilent: Prep 1200, trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA,MWD, Prep benzimidazol-5-yl)propanoate, FC; Column: Chiralpak IA 5 μmenantiomer A 250 × 20 mm; Solvent: hexane/2- propanol 72:28; Flow: 15mL/min; Temperature: rt; Solution: 140 mg/ 2 mL DCM/MeOH 1:1; Injection:14 × 0.15 mL; Detection: UV 254 nm; Analysis: System: Agilent1260/Agilent 1290; Column: Chiralpak IA 3 μm 100 × 4.6 mm; Solvent:hexane/2- propanol 69:31; Flow: 1.0 mL/min; Temperature: 25° C.;Solution: 1.0 mg/mL EtOH/MeOH 1:1; Injection: 5.0 μl; Detection: DAD 254nm: R_(t) = 4.23 min. 2-173-2 methyl 3-(2-{[4-(propan-2- R_(t) = 7.79min (#2). yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate, enantiomer B

Example 2-116 (±)(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide

500 mg (1.01 mmol) (±)5-Bromo-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-61), 140 mg (2.02 mmol) acrylamide, 52 mg (0.17mmol) tri-2-tolylphosphine and 22.6 mg (0.10 mmol) palladium(II) acetatewere dissolved in 7 ml acetonitrile. After addition of 116.2 mg (1.15mmol) triethylamine the reaction mixture was heated in the microwaveoven at 110° C. for one hour. After completion of the reaction thereaction mixture was poured into a mixture ofwater/NH₄Cl/dichloromethane and vigorously stirred. The organic phasewas separated, washed with brine and dried. After evaporation of thesolvent the residue was purified by HPLC yielding 52.7 mg (10%) of thetitle compound.

UPLC-MS: R_(t)=1.28 min; m/z=487.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.89-1.18 (m, 10H), 1.31-1.50 (m,2H), 1.69-1.95 (m, 3H), 2.04 (t, 1H), 4.66 (t, 1H), 6.51 (d, 1H), 6.99(br. s., 1H), 7.23 (d, 1H), 7.33 (d, 2H), 7.41-7.51 (m, 2H), 7.52-7.62(m, 2H), 7.82 (d, 2H), 9.11 (s, 1H).

Example 2-116-1(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide,enantiomer A

The racemic compound (±)(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide(example 2-116; 42 mg in 1.5 mL dichloromethane/N,N-dimethylformamide2:1) was separated via SFC (system: Sepiatec Prep SFC100; column:Chiralpak IA, 5 μM 250×20 mm; injection: 42 mg in 1×0.5 mL and 4×0.25 mLdichloromethane/dimethylformamide 2:1; solvent:CO₂/2-propanol/diethylamine (0.2%) (70:30); flow: 80 mL/min; pressure:100 bar; temperature: 40° C.; detection: UV 254 nm) into its enantiomersyielding 14.1 mg of the title compound (enantiomer A, retention timerange: 3.0-3.6 min; purity 93%) and 19.7 mg of enantiomer B, describedin example 2-116-2.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.89-1.18 (m, 10H), 1.31-1.50 (m,2H), 1.69-1.95 (m, 3H), 2.04 (t, 1H), 4.66 (t, 1H), 6.51 (d, 1H), 6.99(br. s., 1H), 7.23 (d, 1H), 7.33 (d, 2H), 7.41-7.51 (m, 2H), 7.52-7.62(m, 2H), 7.82 (d, 2H), 9.11 (s, 1H).

Example 2-116-2(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide,enantiomer B

The racemic compound (±)(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide(example 2-116; 42 mg in 1.5 mL dichloromethane/dimethylformamide 2:1)was separated via SFC (system: Sepiatec Prep SFC100; column: ChiralpakIA, 5 μM 250×20 mm; injection: 42 mg in 1×0.5 mL and 4×0.25 mLdichloromethane/dimethylformamide 2:1; solvent:CO₂/2-propanol/diethylamine (0.2%) (70:30); flow: 80 mL/min; pressure:100 bar; temperature: 40° C.; detection: UV 254 nm) into its enantiomersyielding 19.7 mg of the title compound (enantiomer B, retention timerange: 3.9-5.0 min; purity 82%) and 14.1 mg of enantiomer A, describedin example 2-116-1.

Example 2-117 (±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide

200 mg (0.41 mmol) (±)(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide(example 2-116) were dissolved in 10 mL ethanol. 21.9 mg (0.2 mmol) Pd/Cwere added and the reaction mixture was stirred under an H₂ atmosphereat room temperature for 12 hours. The catalyst was filtered off via aglass fibre filter, the solvent was evaporated and the residue purifiedby column chromatography yielding 172.1 mg (81%) of the desiredcompound.

UPLC-MS: R_(t)=1.15 min; m/z=489.2 (ES+, M+1).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.87-1.12 (m, 10H), 1.32-1.45 (m,2H), 1.66-1.94 (m, 3H), 1.96-2.11 (m, 1H), 2.30-2.41 (m, 2H), 2.77-2.88(m, 2H), 4.61 (t, 1H), 6.59-6.74 (m, 1H), 6.86 (dd, 1H), 7.17-7.33 (m,4H), 7.40 (d, 1H), 7.73-7.83 (m, 2H), 8.95 (s, 1H).

Example 2-117-13-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide,enantiomer A

The racemic compound (±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide(example 2-117; 140 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM250×20 mm; injection: 140 mg in 5×0.4 mL methanol; solvent: hexane,2-propanol (70:30) and 0.1% diethylamine; flow: 31 mL/min; detection: UV254 nm) into its enantiomers yielding 60 mg of the title compound(enantiomer A, retention time range: 4.0-6.75 min) and 60 mg ofenantiomer B, described in example 2-117-2.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.89-1.15 (m, 10H), 1.38 (d, 2H),1.66-1.92 (m, 3H), 2.02 (t, 1H), 2.35 (t, 2H), 2.83 (t, 2H), 4.61 (br.s., 1H), 6.73 (br. s., 1H), 6.86 (dd, 1H), 7.18-7.34 (m, 4H), 7.41 (d,1H), 7.72-7.84 (m, 2H), 8.97 (s, 1H).

Example 2-117-2 3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide, enantiomer B

The racemic compound (±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide(example 2-117; 140 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Prep FC; column: Chiralpak IA, 5 μM250×20 mm; injection: 140 mg in 5×0.4 mL methanol; solvent: hexane,2-propanol (70:30) and 0.1% diethylamine; flow: 31 mL/min; detection: UV254 nm) into its enantiomers yielding 60 mg of the title compound(enantiomer B, retention time range: 7.5-11 min) and 60 mg of enantiomerA, described in example 2-117-1.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.91-1.13 (m, 10H), 1.39 (d, 2H),1.69-1.93 (m, 3H), 2.03 (s, 1H), 2.35 (t, 2H), 2.83 (t, 2H), 4.61 (br.s., 1H), 6.72 (br. s., 1H), 6.82-6.90 (m, 1H), 7.19-7.34 (m, 4H), 7.41(d, 1H), 7.72-7.83 (m, 2H), 8.97 (s, 1H).

Example 2-118 (±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid

120 mg (0.24 mmol) (±) Methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate(example 2-114) were dissolved in 1 mL dioxane. 11.4 mg (0.48 mmol) LiOHand 0.34 mL water were added and the reaction was stirred at 70° C. fortwo and a half hours. The reaction mixture was evaporated to dryness andthe residue suspended in water. After acidification of the mixture withaqueous HCl (1M) until a pH of 4 the resulting precipitate was filteredoff, washed with water and dried yielding 90.3 mg (74%) of the titlecompound.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.85-1.15 (m, 10H), 1.32-1.54 (m,2H), 1.64-1.88 (m, 3H), 2.04 (t, 1H), 2.42-2.61 (m, 2H, partiallyobscured by the signals of the solvent), 2.86 (t, 2H), 4.69 (br. s.,1H), 6.98 (d, 1H), 7.23 (s, 1H), 7.37 (d, 2H), 7.54 (d, 1H), 7.73 (d,2H), 9.65 (br. s., 1H), 12.10 (br. s., 1H).

Example 2-118-13-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer A

214 mg (0.43 mmol) Methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A (example 2-114-1) were saponified as described in theprevious example 2-118 yielding 177.1 mg (81%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.88-1.12 (m, 10H), 1.33-1.47 (m,2H), 1.66-1.92 (m, 3H), 2.03 (t, 1H), 2.43-2.60 (m, 2H, partiallyobscured by the signals of the solvent), 2.85 (t, 2H), 4.63 (t, 1H),6.91 (d, 1H), 7.22 (s, 1H), 7.32 (d, 2H), 7.45 (d, 1H), 7.76 (d, 2H),9.13 (br. s., 1H), 12.06 (br. s., 1H).

Another batch of3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer A was additionally characterized by specific opticalrotation: [α]_(D) ²⁰=18.3°+/−0.25° (C=1.0000 g/100 mL, methanol).

Example 2-118-23-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer B

200 mg (0.4 mmol) Methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B (example 2-114-2) were saponified as described in example2-118 yielding 168.2 mg (82%) of the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.89-1.18 (m, 10H), 1.32-1.52 (m,2H), 1.66-1.92 (m, 3H), 2.04 (t, 1H), 2.44-2.60 (m, 2H, partiallyobscured by the signals of the solvent), 2.86 (t, 2H), 4.66 (t, 1H),6.95 (d, 1H), 7.22 (s, 1H), 7.35 (d, 2H), 7.50 (d, 1H), 7.73 (d, 2H),9.40 (br. s., 1H), 12.06 (br. s., 1H).

Another batch of3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer B was additionally characterized by specific opticalrotation: [α]_(D) ²⁰=−18.5°+/−0.09° (C=1.0000 g/100 mL, methanol).

Example 2-119 (±)3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoic acid

105 mg (0.22 mmol) (±) Methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate(example 2-115) were dissolved in 0.9 mL dioxane. 10.3 mg (0.43 mmol)LiOH and 0.31 mL water were added and the reaction was stirred at 70° C.for two and a half hours. The reaction mixture was evaporated to drynessand the residue diluted with water. The mixture was acidified withaqueous HCl (1M) until a pH of 4. The resulting precipitate was filteredoff, washed with water and dried yielding 35 mg (33%) of the titlecompound.

UPLC-MS: R_(t)=1.27 min; m/z=474.2 (ES+, M+1).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.88-1.05 (m, 10H), 1.35-1.47 (m,2H), 1.70-1.95 (m, 3H), 2.04 (t, 1H), 2.40-2.64 (m, 2H, partiallyobscured by the signal of the solvent), 2.86 (t, 2H), 4.60-4.70 (m, 1H),6.90 (d, 1H), 7.29 (d, 1H), 7.47 (d, 1H), 7.64 (d, 2H), 7.88 (d, 2H),9.21 (br., 1H), 12.2 (very br., 1H).

Example 2-119-13-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer A

In analogy to example 2-165-1: Methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A (example 2-115-1; 159 mg, 0.326 mmol) was reacted withlithium iodide (5.0 eq., 218 mg, 1.63 mmol) in pyridine (5 mL) at 125°C. for 5 days to give after preparative HPLC the title compound (41 mg,25%).

UPLC-MS (ESI+): [M+H]⁺=474; R_(t)=0.99 min (Method F).

Example 2-119-23-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer B

In analogy to example 2-165-1: Methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B (example 2-115-2; 139 mg, 0.285 mmol) was reacted withlithium iodide (5.0 eq., 191 mg, 1.43 mmol) in pyridine (4 mL) at 125°C. for 5 days to give after preparative HPLC the title compound (22 mg,15%).

UPLC-MS (ESI+): [M+H]⁺=474; R_(t)=0.99 min (Method F).

The examples in Table 4 were prepared in an analogous manner toreference example 2-26, starting from the given ester precursors.

TABLE 4 Ester Example Structure/Name Analytical data precursor 2-174

 

  (±) 3-(2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoic acid ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.96 (d, 3H), 1.02 (s, 3H), 1.07 (s, 3H),1.11-1.14 (m, 1H), 1.31 (d, 6H), 1.36-1.39 (m, 1H), 1.60-1.63 (m, 1H),1.68- 1.77 (m, 1H), 1.88-1.98 (m, 2H), 2.09 (t, 1H), 2.50-2.55 (m, 2H),2.87-2.90 (m, 2H), 4.66 (sept, 1H), 4.76-4.82 (m, 1H), 7.06-7.08 (m,2H), 7.15 (d, 1H), 7.18 (s, 1H), 7.39-7.41 (m, 2H), 7.72 (d, 1H), 10.65(br. s., 0.8H*), 12.14 (br. s., 1H), 12.59 (br. s., 0.9H*). UPLC-MS(ESI+): [M + H]⁺ = 464; R_(t) = 0.95 min (Method F). Example 2-1722-174-1 3-(2-{[4-(propan-2- UPLC-MS (ESI+): [M + H]⁺ = Exampleyloxy)phenyl]amino}-1-[(cis)- 464; R_(t) = 0.93 min (Method 2-172-13,3,5-trimethylcyclohexyl]-1H- F). benzimidazol-5-yl)propanoic acid,enantiomer A 2-174-2 3-(2-{[4-(propan-2- UPLC-MS (ESI+): [M + H]⁺ =Example yloxy)phenyl]amino}-1-[(cis)- 464; R_(t) = 0.92 min (Method2-172-2 3,3,5-trimethylcyclohexyl]-1H- F). benzimidazol-5-yl)propanoicacid, enantiomer B 2-175

 

  (±) 3-(2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoic acid ¹H-NMR (400MHz, DMSO- d₆): δ [ppm] = 0.96 (d, 3H), 1.01 (s, 3H), 1.06 (s, 3H),1.11-1.17 (m, 1H), 1.25 (d, 6H), 1.36-1.39 (m, 1H), 1.58-1.61 (m, 1H),1.69- 1.78 (m, 1H), 1.86-1.98 (m, 2H), 2.08 (t, 1H), 2.52-2.56 (m, 2H),2.87-2.91 (m, 2H), 2.96 (sept, 1H), 4.80-4.86 (m, 1H), 7.15 (d, 1H),7.22 (s, 1H), 7.37-7.44 (m, 4H), 7.73 (d, 1H), 10.76 (br. s., 0.8H*),12.15 (br. s., 0.9H*), 12.85 (br. s., 0.8H*). UPLC-MS (ESI+): [M + H]⁺ =448; R_(t) = 1.01 min (Method F). Example 2-173 2-175-13-(2-{[4-(propan-2- UPLC-MS (ESI+): [M + H]⁺ = 2-173-1yl)phenyl]amino}-1-[(cis)-3,3,5- 448; R_(t) = 0.93 min (Methodtrimethylcyclohexyl]-1H- B). benzimidazol-5-yl)propanoic acid,enantiomer A 2-175-2 3-(2-{[4-(propan-2- UPLC-MS (ESI+): [M + H]⁺ =2-173-2 yl)phenyl]amino}-1-[(cis)-3,3,5- 448; R_(t) = 0.93 min (Methodtrimethylcyclohexyl]-1H- B). benzimidazol-5-yl)propanoic acid,enantiomer B

Example 2-120(±)-(2E)-N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide

200 mg (0.40 mmol) (±)5-Bromo-N-[4-(trifluoromethoxy)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-61), 80 mg (0.81 mmol) N,N-dimethylacrylamide, 20.8mg (0.07 mmol) tri-2-tolylphosphine and 9 mg (0.04 mmol) palladium(II)acetate were dissolved in 2.8 ml acetonitrile. After addition of 46.5 mg(0.46 mmol) triethylamine the reaction mixture was heated in themicrowave oven at 110° C. for one hour and after completion of thereaction poured into a mixture of water/NH₄Cl/dichloromethane andvigorously stirred. The organic phase was separated, washed with brineand dried. After evaporation of the solvent the residue was purified bycolumn chromatography (silicagel, eluents: ethyl acetate/hexane)yielding 65.4 mg (30%) of the title compound.

UPLC-MS: R_(t)=1.37 min; m/z=515.3 (ES+, M+1).

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.91-1.13 (m, 10H), 1.38-1.46 (m,2H), 1.72-1.98 (m, 3H), 2.04 (t, 1H), 2.92 (s, 3H), 3.15 (s, 3H),4.60-4.71 (m, 1H), 7.12 (d, 1H), 7.26-7.38 (m, 3H), 7.47-7.57 (m, 2H),7.80-7.90 (m, 3H), 9.10 (s, 1H).

Example 2-121 (±)N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide

50 mg (0.097 mmol)(±)-(2E)-N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide,prepared in the previous example 2-120, was dissolved in 2.4 mL ethanol.After addition of 5.2 mg (0.05 mmol) Pd/C (10%) the reaction mixture wasstirred at room temperature for 12 hours under an H₂ atmosphere. Afterfiltration of the catalyst via a glass fibre filter the solvent wasevaporated yielding 31.3 mg (56%) of the title compound which was 90%pure.

UPLC-MS: R_(t)=1.27 min; m/z=517.3 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.91-1.09 (m, 10H), 1.30-1.43 (m,2H), 1.67-1.94 (m, 3H), 2.03 (t, 1H), 2.50-2.66 (m, 2H, partiallyobscured by the signal of the solvent), 2.80-2.90 (m, 5H), 2.92 (s, 3H),4.52-4.70 (m, 1H), 6.89 (d, 1H), 7.21-7.34 (m, 3H), 7.41 (d, 1H), 7.78(d, 2H), 8.98 (br. s., 1H).

Example 2-122 (±)({2-[(4-ethoxyphenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid

Step 1

(±) tert-butyl({2-[(4-ethoxyphenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)acetate250 mg (0.69 mmol) (±) tert-Butyl(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenoxy)-acetate(intermediate 1-3) were dissolved in 2 mL tetrahydrofurane. 124 mg (0.69mmol) 1-Ethoxy-isothiocyanatobenzene and 174 mg (1.38 mmol)N,N′-diisopropylcarbodiimide were added and the reaction mixture wasstirred at 70° C. overnight. The solvent was removed and the residue waspurified twice by column chromatography (Biotage, eluents: hexane/ethylacetate) yielding 140 mg (39%) of the desired product.

UPLC-MS: R_(t)=1.61 min; m/z=509.3 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.89-1.11 (m, 10H), 1.24-1.52 (m,14H), 1.61-1.92 (m, 3H), 1.94-2.07 (m, 1H), 3.91-4.07 (m, 2H), 4.49-4.59(m, 3H), 6.55 (dd, 1H), 6.80-6.93 (m, 3H), 7.33 (d, 1H), 7.55 (d, 2H),8.55 (s, 1H).

Step 2: (±)({2-[(4-ethoxyphenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid

100 mg (0.2 mmol) (±) tert-Butyl({2-[(4-ethoxyphenyl)amino]-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl}oxy)acetate,described in step 1, were dissolved in 46.4 mL HCl in dioxane (4M) andstirred at room temperature for three days. The reaction mixture wasevaporated to dryness and the residue was treated was treated withsaturated sodium hydrogencarbonate solution (pH 9). After stirring atroom temperature for one hour a solid precipitated. Dichloromethane (100mL) was added. After stirring for 45 min the organic phase was separatedand washed with water and brine. The organic phase was dried (sodiumsulfate), filtrated and the solvent was removed. The UPLC-MS showedproduct. The residue was given in water and acidified with hydrochloricacid (1N) until a pH of 4. The resulting suspension was stirred at roomtemperature overnight and filtrated off the next day. The precipitatewas purified by chromatography yielding 14.1 mg (15%) of the titlecompound.

UPLC-MS: R_(t)=1.13 min; m/z=452.0 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.85-1.12 (m, 10H), 1.23-1.46 (m,5H), 1.61-1.86 (m, 3H), 2.00 (t, 1H), 3.98 (q, 2H), 4.48-4.65 (m, 3H),6.57 (dd, 1H), 6.78-6.93 (m, 3H), 7.33 (d, 1H), 7.56 (d, 2H), 8.53 (br.s., 1H), 12.86 (br. s., 1H).

The examples in Table 5 were analogously prepared in two steps startingfrom intermediate 1-3 and the corresponding commercially availableisothiocyanates as described in the previous example 2-122, however thework-up was changed. After completion of the reaction the reactionmixture was evaporated to dryness and the residue purified by columnchromatography.

TABLE 5 Example/ UPLC- Isothiocya- MS resp. nate Structure/Name ¹H-NMRMS 2-123 1- isothiocya- nato-4- (trifluoro- methoxy)ben- zene, CAS No.:64285-95- 6

 

  (±) [(2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]acetic acid(300 MHz, DMSO-d₆): δ [ppm] = 0.88-1.12 (m, 10H), 1.39 (d, 2H),1.65-1.92 (m, 3H), 2.01 (t, 1H), 4.51-4.67 (m, 3H), 6.64 (dd, 1H), 6.90(d, 1H), 7.29 (d, 2H), 7.41 (d, 1H), 7.76 (d, 2H), 8.96 (br. s., 1H),12.87 (br. s., 1H). R_(t) = 1.19 min; m/z = 492.2 (ES+, M + 1). 2-123-1[(2-{[4- (400 MHz, DMSO-d₆): R_(t) = 1.27 (The(trifluoromethoxy)phenyl]amino}-1- δ [ppm] = 0.89-1.19 min; m/z =separation [(cis)-3,3,5-trimethylcyclohexyl]-1H- (m, 10H), 1.29-1.58492.2 of the benzimidazol-5-yl)oxy]acetic acid, (m, 2H), 1.67-1.80 (ES+,racemate enantiomer A (m, 1H), 1.80-1.95 M + 1). into its (m, 2H), 2.03(t, 1H), enantiomers 4.60-4.76 (m, 3H), was 6.73 (d, 1H), 6.90 (s,carried out 1H), 7.38 (d, 2H), on the tert 7.56 (br. s., 1H), butylester 7.71 (d, 2H), 9.65 intermediate) (br. s, 1H), 12.95 (br. s., 1H).2-123-2 [(2-{[4- (400 MHz, DMSO-d₆): R_(t) = 1.25 (The(trifluoromethoxy)phenyl]amino}-1- δ [ppm] = 0.89-1.18 min; m/z =separation [(cis)-3,3,5-trimethylcyclohexyl]-1H- (m, 10H), 1.31-1.58492.2 of the benzimidazol-5-yl)oxy]acetic acid, (m, 2H), 1.67-1.80 (ES+,racemate enantiomer B (m, 1H), 1.80-1.95 M + 1). into its (m, 2H), 2.03(t, 1H), enantiomers 4.60-4.74 (m, 3H), was 6.73 (d, 1H), 6.90 (s,carried out 1H), 7.38 (d, 2H), on the tert 7.56 (br. s., 1H), butylester 7.71 (d, 2H), 9.55 intermediate) (br. s, 1H), 12.95 (br. s., 1H).2-124 1- isothiocya- nato-4- (propan-2- yloxy)ben- zene, CAS No.:50785-46- 1

 

  (±) ({2-[(4-isopropoxyphenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl}oxy)acetic acid(300 MHz,DMSO-d₆): δ [ppm] = 0.88-1.10 (m, 10H), 1.25 (d, 6H), 1.38 (d,2H), 1.58-1.89 (m, 3H), 2.00 (t, 1H), 4.41- 4.66 (m, 4H), 6.57 (dd, 1H),6.77-6.93 (m, 3H), 7.33 (d, 1H), 7.54 (d, 2H), 8.53 (br. s., 1H), 12.85(br. s., 1H). R_(t) = 1.15 min; m/z = 466.3 (ES+, M + 1). 2-125 4-isothiocya- natobenzo- nitrile, CAS No.: 2719-32-6

 

  (±) ({2-[(4-cyanophenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl}oxy)acetic acid(300 MHz, DMSO-d₆): δ [ppm] = 0.84-1.18 (m, 10H), 1.39 (d, 2H),1.68-1.88 (m, 3H),2.01 (t, 1H), 4.58-4.70 (m, 3H), 6.69 (dd, 1H), 6.97(d, 1H), 7.47 (d, 1H), 7.72 (d, 2H), 7.82 (d, 2H), 9.37 (br. s., 1H),12.90 (br. s., 1H). R_(t) = 1.14 min; m/z = 433.2 (ES+, M + 1).

Example 2-127 (±) methylN-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate

0.30 g (0.52 mmol) (±)[(2-{[4-(Trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid (example 2-123) were dissolved in 3.2 mL N,N-dimethylformamide.0.08 g (0.62 mmol) Methyl glycinate hydrochloride, suspended in 0.5 mLDMF, and 0.054 mL triethylamine were added. After addition of 0.32 g(0.62 mmol) PyBOP and 0.27 mL (1.56 mmol) Hünig's base the reactionmixture was stirred at room temperature for three days. The reactionmixture was diluted with water (20 mL) and was extracted twice withmethyl-tert.butylether (80 mL each). The combined organic phases werewashed with water and brine. After drying over sodium sulfate thesolvent was evaporated and the residue was purified by columnchromatography (silicagel, eluents: hexane/ethyl acetate) yielding 0.18g (59%) of the desired compound.

UPLC-MS: R_(t)=1.23 min; m/z=564.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.89-1.13 (m, 10H), 1.39 (d, 2H),1.64-1.94 (m, 3H), 2.02 (t, 1H), 3.62 (s, 3H), 3.92 (d, 2H), 4.47-4.70(m, 3H), 6.72 (dd, 1H), 7.00 (d, 1H), 7.30 (d, 2H), 7.45 (d, 1H), 7.78(d, 2H), 8.49 (t, 1H), 9.00 (s., 1H).

Example 2-128 (±)N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide

0.30 g (0.52 mmol) (±)[(2-{[4-(Trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid (example 2-123) were dissolved in 3.2 mL N,N-dimethylformamide.0.04 g (0.62 mmol) Cyclopropylamine, 0.32 g (0.62 mmol) PyBOP and 0.27mL (1.56 mmol) Hünig's base were added and the reaction mixture wasstirred at room temperature for three days. The reaction mixture wasdiluted with water (20 mL) and was extracted twice withmethyl-tert.butylether (80 mL each). The combined organic phases werewashed with water and brine. After drying over sodium sulfate thesolvent was evaporated and the residue was purified by columnchromatography (silicagel, eluents: hexane/ethyl acetate) yielding 0.17g (60%) of the desired title compound as racemate.

UPLC-MS: R_(t)=1.31 min; m/z=532.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.45-0.53 (m, 2H), 0.56-0.68 (m, 2H),0.89-1.15 (m, 10H), 1.40 (d, 2H), 1.65-1.98 (m, 3H), 2.02 (t, 1H),2.61-2.77 (m, 1H), 4.40 (s, 2H), 4.52-4.70 (m, 1H), 6.69 (dd, 1H), 6.96(d, 1H), 7.30 (d, 2H), 7.42 (d, 1H), 7.71-7.85 (m, 2H), 8.09 (d, 1H),8.99 (s, 1H).

Example 2-128-1N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide,enantiomer A

The racemic compound (±)N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide(example 2-128; 131 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Gilson: Liquid Handler 215; column:Chiralpak IA, 5 μM 250×20 mm; injection: 131 mg in 1×0.4 mL and 2×0.8 mLdichloromethane; solvent: hexane, 2-propanol (70:30) and 0.1%diethylamine; flow: 20 mL/min; detection: UV 254 nm) into itsenantiomers yielding 52 mg of the title compound (enantiomer A,retention time range: 9.0-11.2 min) and 56 mg of enantiomer B, describedin example 2-128-2.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.45-0.53 (m, 2H), 0.58-0.69 (m, 2H),0.90-1.15 (m, 10H), 1.39 (d, 2H), 1.63-1.94 (m, 3H), 2.01 (t, 1H),2.62-2.78 (m, 1H), 4.40 (s, 2H), 4.52-4.69 (m, 1H), 6.69 (dd, 1H), 6.94(d, 1H), 7.30 (d, 2H), 7.43 (d, 1H), 7.71-7.85 (m, 2H), 8.09 (d, 1H),8.98 (s, 1H).

Example 2-128-2N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide,enantiomer B

The racemic compound (±)N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide(example 2-128; 131 mg) was separated via chiral HPLC (system: AgilentPrep 1200, 2×Prep Pump, DLA, MWD, Gilson: Liquid Handler 215; column:Chiralpak IA, 5 μM 250×20 mm; injection: 131 mg in 1×0.4 mL and 2×0.8 mLdichloromethane; solvent: hexane, 2-propanol (70:30) and 0.1%diethylamine; flow: 20 mL/min; detection: UV 254 nm) into itsenantiomers yielding 56 mg of the title compound (enantiomer B,retention time range: 13.0-15.4 min) and 52 mg of enantiomer A,described in example 2-128-1.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.45-0.53 (m, 2H), 0.56-0.68 (m, 2H),0.89-1.15 (m, 10H), 1.38 (d, 2H), 1.65-1.92 (m, 3H), 2.01 (t, 1H),2.61-2.75 (m, 1H), 4.40 (s, 2H), 4.51-4.68 (m, 1H), 6.68 (dd, 1H), 6.94(d, 1H), 7.30 (d, 2H), 7.42 (d, 1H), 7.71-7.85 (m, 2H), 8.09 (d, 1H),8.98 (s, 1H).

The corresponding amides in Table 6 were prepared in analogy to thesynthesis of the amide described in Example 2-128 using PyBOP and thecorresponding amines.

TABLE 6 Example Structure/Name Analytical data 2-256

 

  (±) N,N-dimethyl-2-[(2-{[4- trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]acetamide¹H-NMR (300 MHz, DMSO-d₆): δ [ppm] = 0.89-1.12 (m, 10H), 1.39 (d, 2H),1.63-2.09 (m, 4H), 2.82 (s, 3H), 3.01 (s, 3H), 4.52- 4.68 (m, 1H), 4.76(s, 2H), 6.63 (dd, 1H), 6.98 (d, 1H), 7.30 (d, 2H), 7.41 (d, 1H), 7.78(d, 2H), 8.99 (s, 1H). UPLC-MS: R_(t) = 1.24 min; m/z = 520.2 (ES+, M +1). 2-256-1 N,N-dimethyl-2-[(2-{[4- The separation was carried outtrifluoromethoxy)phenyl]amino}-1- twice due to insufficient purity after[(cis)-3,3,5-trimethylcyclohexyl]-1H- the first run.benzimidazol-5-yl)oxy]acetamide, Separation: enantiomer A System:Sepiatec: Prep SFC100; Column: Chiralpak IA 5 μm 250 × 20 mm; Solvent:CO₂/2-propanol 70:30; Pressure (outlet): 150 bar; Flow: 80 mL/min;Temperature: 40° C.; Solution: 149 mg/2 mL acetone/ethyl acetate 1:1;Injection: 20 × 0.1 mL; Detection: UV 254 nm; R_(t) = 7.1-9.2 min.Analysis: System: Agilent: 1260 AS, MWD, Aurora SFC Modul; Column:Chiralpak IA 5 μm 100 × 4.6 mm; Solvent: CO₂/2-propanol 70:30; Flow: 4.0mL/min; Pressure: 100 bar; Temperature: 37.5° C.; Solution: 1.0 mg/mLEtOH/MeOH 1:1; Injection: 10.0 μL; Detection: DAD 254 nm: R_(t) = 2.98min. 2-256-2 N,N-dimethyl-2-[(2-{[4- Separation: R_(t) = 9.8-14.5 min.trifluoromethoxy)phenyl]amino}-1- Analysis: R_(t) = 4.22 min.[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]acetamide,2-257

 

  (±) N-cyclopropyl-N-methyl-2-[(2- {[4-trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]- 1H-benzimidazol-5- yl)oxy]acetamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.75-0.88 (m, 4H), 0.90- 1.13 (m,10H), 1.32-1.45 (m, 2H), 1.65-1.95 (m, 3H), 2.02 (t, 1H), 2.78-2.95 (m,4H), 4.52- 4.68 (m, 1H), 4.89 (s, 2H), 6.62 (dd, 1H), 6.91 (d, 1H), 7.32(d, 2H), 7.39 (d, 1H), 7.78 (d, 2H), 8.97 (s, UPLC-MS (Method B): R_(t)= 1.54 min; m/z = 545.3 (ES+, M + 1). 2-257-1N-cyclopropyl-N-methyl-2-[(2-{[4- Separation:trifluoromethoxy)phenyl]amino}-1- System: Agilent: Prep 1200,[(cis)-3,3,5-trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)oxy]acetamide, FC; Column: Chiralpak IC 5 μmenantiomer A 250 × 30 mm; Solvent: hexane/2- ethanol/diethylamine70:30:0.1; Flow: 50 mL/min; Temperature: rt; Solution: 135 mg/1.5 mLDCM/ MeOH 1:1; Injection: 5 × 0.3 mL; Detection: UV 254 nm; R_(t) =14.2-15.5 min Analysis: System: Waters: Alliance 2695, DAD 996, ESA:Corona; Column: Chiralpak IC 3 μm 100 × 4.6 mm; Solvent: hexane/ethanol/diethylamine 70:30:0.1; Flow: 1.0 mL/min; Temperature: 25° C.; Solution:1.0 mg/mL EtOH/MeOH 1:1; Injection: 5.0 pL; Detection: DAD 254 nm: R_(t)= 5.78 min. 2-257-2 N-cyclopropyl-N-methyl-2-[(2-{[4- Separation: R_(t)= 16.1-17.8 min. trifluoromethoxy)phenyl]amino}-1- Analysis: R_(t) =7.15 min. [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide, enantiomer B

Example 2-129 (±)N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine

0.145 g (0.26 mmol) (±) MethylN-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate(example 2-127) were suspended in 1.1 mL dioxane. After addition of0.012 g (0.52 mmol) lithium hydroxide and 0.37 mL water the reactionmixture was stirred at 70° C. for five hours. The solvent was removedand the reaction mixture suspended in water (20 mL). The pH of themixture was adjusted to pH 4 by addition of 1M HCl. The mixture was thenstirred at room temperature overnight. The precipitate was filtered off,washed with water and subsequently dried yielding 0.13 g of a mixture ofthe title compound and (±)[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid (example 2-123). Consequently, the mixture was further purified byHPLC yielding finally 66.9 mg (44%) of the desired compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.91-1.07 (m, 10H), 1.38 (d, 1H),1.56 (d, 1H), 1.66-1.98 (m, 3H), 2.05 (t, 1H), 3.81 (d, 2H), 4.54 (s,2H), 4.65 (t, 1H), 6.89 (d, 1H), 6.96 (d, 1H), 7.45 (d, 2H), 7.59-7.76(m, 3H), 8.40 (t, 1H), 10.05 (very br.), 12.6 (very br.).

Example 2-130 (±) methylN-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate

0.30 g (0.52 mmol) (±)[(2-{[4-(Trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid (example 2-123) were dissolved in 3.2 mL N,N-dimethylformamide.0.09 g (0.62 mmol) Methyl N-methylglycinate hydrochloride, 0.32 g (0.62mmol) PyBOP and 0.27 mL (1.56 mmol) Hünig's base were added and thereaction mixture was stirred at room temperature for three days. Thereaction mixture was diluted with water (20 mL) and extracted twice withmethyl-tert.butylether (80 mL each). The combined organic phases werewashed with water and brine. After drying over sodium sulfate thesolvent was evaporated and the residue was purified by columnchromatography (silicagel, eluents: hexane/ethyl acetate) yielding 0.12g (38.8%) of the desired title compound as racemate.

UPLC-MS: R_(t)=1.31 min; m/z=578.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.89-1.13 (m, 10H), 1.39 (d, 2H),1.62-1.96 (m, 3H), 2.01 (t, 1H), 2.88 and 3.09 (s, combined 3H), 3.65and 3.70 (s, combined 3H), 4.10 and 4.31 (s, combined 2H), 4.52-4.70 (m,1H), 4.70 and 4.83 (s, combined 2H), 6.58-6.69 (m, 1H), 6.91-7.00 (m,1H), 7.30 (d, 2H), 7.41 (d, 1H), 7.79 (d, 2H), 8.99 (s., 1H).

Example 2-131 (±)N-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine

90 mg (0.16 mmol) (±) MethylN-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate(example 2-130) were saponified as described in example 2-129 yielding20.9 mg (23%) of the title compound after purification via HPLC.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.90-1.19 (m, 10H), 1.38 (d, 1H),1.54 (d, 1H), 1.62-1.95 (m, 3H), 2.04 (t, 1H), 2.83 and 3.05 (s,combined 3H), 3.99 and 4.19 (s, combined 2H), 4.55-4.68 (m, 1H), 4.73and 4.88 (s, combined 2H), 6.70-7.92 (m, 2H), 7.44 (br., d, 2H),7.53-7.75 (m, 3H), 12.66 (br. s., 1H).

Example 2-132 (±)4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid

Step 1

(±) tert-butyl4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoate295 mg (0.75 mmol) (±) tert-Butyl4-(3-amino-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenoxy)butanoate(intermediate 1-9) were dissolved in 15 mL tetrahydrofurane. 165.5 mg(0.75 mmol) 1-Isothiocyanato-4-(trifluoromethoxy)benzene and 190.6 mg(1.51 mmol) N,N′-diisopropylcarbodiimide were added and the reactionmixture was stirred at 70° C. for five hours. The solvent was removedand the residue was purified twice by column chromatography (Biotage,eluents: hexane/ethyl acetate) yielding 310 mg (68%) of the desiredproduct.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.89-1.10 (m, 10H), 1.32-1.44 (m,11H), 1.66-1.78 (m, 1H), 1.78-2.05 (m, 5H), 2.36 (t, 2H), 3.95 (t, 2H),4.53-4.66 (m, 1H), 6.62 (dd, 1H), 6.95 (d, 1H), 7.29 (d, 2H), 7.39 (d,1H), 7.71-7.81 (m, 2H), 8.95 (s, 1H).

Step 2: (±)4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid

100 mg (0.17 mmol) (±) tert-Butyl4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoate,described in step 1, were dissolved in 4.3 mL HCl in dioxane (4M) andstirred at room temperature for 21 hours. The reaction mixture wasevaporated to dryness and the residue was treated with water. Theresulting suspension was stirred at room temperature overnight, thesolid filtrated off and dried at air to give 86.4 mg (86%) of the titlecompound which was slightly contaminated.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.91-1.18-1.30 (m, 10H), 1.30-1.43(m, 1H), 1.51 (d, 1H), 1.71 (q, 1H), 1.80-2.08 (m, 5H), 2.38 (t, 2H),3.98 (t, 2H), 4.70 (br. s., 1H), 6.77 (d, 1H), 6.91 (d, 1H), 7.41 (d,2H), 7.58 (br. s., 1H), 7.68 (d, 2H), 12.10 (br. s., 1H).

The examples in Table 7 were analogously prepared in two steps asdescribed in example 2-132 starting from intermediate 1-9 and thecorresponding commercially available isothiocyanates and whereappropriate separated into their enantiomers. The separation of theracemates into their enantiomers was carried out on the tert butylesterintermediate.

TABLE 7 Example/ Isothio- Methods/ cyanate Structure/Name Analyticaldata 2-132-1

 

  4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]butanoicacid, enantiomer A System: Agilent Prep 1200, 2 × Prep Pump, DLA, MWD,Gilson: Liquid Handler 215; column: Chiralpak IA, 5 μM 250 × 30 mm;injection: 160 mg in 3 × 0.6 mL dichloromethane; solvent: hexane,2-propanol (70:30) and 0.1% diethylamine; flow: 45 mL/min; detection: UV254 nm; R_(t) = 6.8-8.4 min. UPLC-MS: R_(t) = 1.34 min; m/z = 520.2(ES+, M + 1). 2-132-2

 

  4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]butanoicacid, enantiomer B System: Agilent Prep 1200, 2 × Prep Pump, DLA, MWD,Gilson: Liquid Handler 215; column: Chiralpak IA, 5 μM 250 × 30 mm;injection: 160 mg in 3 × 0.6 mL dichloromethane; solvent: hexane,2-propanol (70:30) and 0.1% diethylamine; flow: 45 mL/min; detection: UV254 nm; R_(t) = 10.2-12.1 min UPLC-MS: R_(t) = 1.32 min; m/z = 520.2(ES+, M + 1). 2-133 1- isothio- cyanato- 4- (propan- 2- yl)benzene, CASNo.: 89007- 45-4

 

(±) 4-[(2-{[4-(isopropyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]butanoicacid ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.15 (m, 9H), 1.18-1.28(m, 7H), 1.37 (d, 1H), 1.55 (d, 1H), 1.70 (q, 1H), 1.78-1.97 (m, 4H),2.04 (t, 1H), 2.40 (t, 2H), 2.93 (dt, 1H), 3.98 (t, 2H), 4.75 (br. s.,1H), 6.81 (d, 1H), 6.87 (d, 1H), 7.27- 7.38 (m, 2H), 7.38-7.50 (m, 2H),7.65 (d, 1H), 12.11 (br. s., 1H). UPLC-MS: R_(t) = 1.24 min; m/z = 478.3(ES+, M + 1). 2-133-1 4-[(2-{[4-(isopropyl)phenyl]amino}-1-[(cis)-Separation: 3,3,5-trimethylcyclohexyl]-1H- System: Agilent: Prep 1200,benzimidazol-5-yl)oxy]butanoic acid, 2 × Prep Pump, DLA, MWD, enantiomerA Gilson: Liquid Handler 215; Column: Chiralpak IA 5 μm 250 × 30 mm;Solvent: hexane/ 2-propanol/diethylamine 70:30:0.1 (v/v/v); Flow: 50mL/min; Temperature: rt; Solution: 66 mg/4.6 mL DCM/MeOH; Injection: 2 ×0.8 mL; Detection: UV 254 nm; Analysis: System: Waters: Alliance 2695,DAD 996, ESA: Corona; Column: Chiralpak IA 3 μm 100 × 4.6 mm; Solvent:hexane/ 2-propanol/diethylamine 70:30:0.1 (v/v/v); Flow: 1.0 mL/min;Temperature: 25° C.; Solution: 1.0 mg/mL EtOH/MeOH 1:1; Injection: 5.0μl; Detection: DAD 254 nm: R_(t) = 4.22 min. UPLC-MS (ESI+): [M + H]⁺ =478; R_(t) = 1.01 min (Method E). 2-133-24-[(2-{[4-(isopropyl)phenyl]amino}-1-[(cis)- R_(t) = 7.78 min.3,3,5-trimethylcyclohexyl]-1H- UPLC-MS (ESI+): [M + H]⁺ =benzimidazol-5-yl)oxy]butanoic acid, 478; R_(t) = 1.00 min (Method E).enantiomer B 2-134 1- isothio- cyanato- 4- (propan- 2- yloxy)ben- zene,CAS No.: 50785- 46-1

 

  (±) 4-[(2-{[4-(isopropoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]butanoicacid ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.91-1.15 (m, 9H), 1.15-1.33(m, 7H), 1.37 (d, 1H), 1.57 (d, 1H), 1.69 (q, 1H), 1.79-2.00 (m, 4H),2.04 (t, 1H), 2.40 (t, 2H), 3.97 (t, 2H), 4.57-4.76 (m, 2H), 6.74- 6.88(m, 2H), 7.03 (d, 2H), 7.41 (d, 2H), 7.63 (d, 1H), 12.12 (br. s., 1H),12.51 (br. s., 1H). UPLC-MS: R_(t) = 1.19 min; m/z = 494.3 (ES+, M + 1).2-135 1- isothio- cyanato- 4- (trifluoro- methyl) benzene, CAS No.:1645- 65-4

 

  (±) 4-[(2-{[4- (trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]butanoic acid¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.91-1.15 (m, 9H), 1.20-1.32 (m,1H), 1.38 (d, 1H), 1.52 (d, 1H), 1.71 (q, 1H), 1.80-2.00 (m, 4H), 2.02(t, 1H), 2.40 (t, 2H), 4.00 (t, 2H), 4.68-4.82 (m, 1H), 6.80 (d, 1H),6.98 (d, 1H), 7.52-7.82 (m, 5H), 10.30 (br., 1H), 12.12 (br. s., 1H).UPLC-MS: R_(t) = 1.29 min; m/z = 504.2 (ES+, M + 1). 2-135-14-[(2-{[4-(trifluoromethyl)phenyl]amino}-1- Agilent Prep 1200, 2 × Prep[(cis)-3,3,5-trimethylcyclohexyl]-1H- Pump, DLA, MWD, Gilson:benzimidazol-5-yl)oxy]butanoic acid, Liquid Handler 215; column:enantiomer A Chiralpak IA, 5 μM 250 × 30 mm; injection: 159 mg in 3 ×0.6 mL dichloromethane; solvent: hexane, 2-propanol (70:30) and 0.1%diethylamine; flow: 45 mL/ min; detection: UV 254 nm; R_(t) = 8.2-9.8min UPLC-MS: R_(t) = 1.34 min; m/z = 504.2 (ES+, M + 1) 2-135-24-[(2-{[4-(trifluoromethyl)phenyl]amino}-1- Agilent Prep 1200, 2 × Prep[(cis)-3,3,5-trimethylcyclohexyl]-1H- Pump, DLA, MWD, Gilson:benzimidazol-5-yl)oxy]butanoic acid, Liquid Handler 215; column:enantiomer B Chiralpak IA, 5 μM 250 × 30 mm; injection: 159 mg in 3 ×0.6 mL dichloromethane; solvent: hexane, 2-propanol (70:30) and 0.1%diethylamine; flow: 45 mL/ min; detection: UV 254 nm; R_(t) = 12.8-15.2min UPLC-MS: R_(t) = 1.33 min; m/z = 504.2 (ES+, M + 1).

Example 2-138 (±) methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)acrylate

500 mg (1.04 mmol) (±)5-Bromo-N-[4-(trifluoromethyl)phenyl]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-amine(reference example 2-62), 179.2 mg (2.08 mmol) methacrylate, 53.9 mg(0.18 mmol) tri-2-tolylphosphine and 23.4 mg (0.1 mmol) palladium(II)acetate were dissolved in 7.3 mL acetonitrile. After addition of 0.17 mL(1.19 mmol) triethylamine the reaction mixture was heated in themicrowave oven at 110° C. for 60 min. Due to an incomplete reactionadditional reagents were added (1 eq. each) and heating was continued ina heating block overnight (110° C.). The reaction mixture was given on aflash column and washed with ethyl acetate (250 mL) to remove thecatalyst and the salts. The filtrate was evaporated to dryness and theresidue was purified by column chromatography yielding 252 mg (47%) ofthe title compound.

UPLC-MS: R_(t)=1.59 min; m/z=486.2 (ES+, M+1).

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.91-1.18 (m, 10H), 1.32-1.50 (m,2H), 1.70-1.98 (m, 3H), 2.08 (t, 1H), 3.72 (s, 3H), 4.71 (br., 1H), 6.58(d, 1H), 7.42 (d, 1H), 7.58-7.88 (m, 5H), 7.93 (d, 2H), 9.38 (s, 1H).

Example 2-138-1 methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate,enantiomer A

97 mg of the racemic compound (±) methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate,described in example 2-138, were separated via chiral HPLC (system:Agilent Prep 1200, 2×Prep Pump, DLA, MWD, Gilson: Liquid Handler 215;column: Chiralpak AD-H, 5 μM 250×30 mm; injection: 97 mg in 3×1 mLethanol/methanol; solvent: ethanol, methanol, diethylamine (50:50:0.1);flow: 30 mL/min; detection: UV 280 nm) into its enantiomers yielding 35mg of the title compound (enantiomer A, R_(t)=9.3-11.6 min) and 35 mg ofenantiomer B, described in example 2-138-2.

Example 2-138-2 methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate,enantiomer B

97 mg of the racemic compound (±) methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate,described in example 2-138, were separated via chiral HPLC (system:Agilent Prep 1200, 2×Prep Pump, DLA, MWD, Gilson: Liquid Handler 215;column: Chiralpak AD-H, 5 μM 250×30 mm; injection: 97 mg in 3×1 mLethanol/methanol; solvent: ethanol, methanol, diethylamine (50:50:0.1);flow: 30 mL/min; detection: UV 280 nm) into its enantiomers yielding 35mg of the title compound (enantiomer B R_(t)=13.6-17.0 min) and 35 mg ofenantiomer A, described in example 2-138-1.

Reference Example 2-150 (±) methyl6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazole-5-carboxylate

A solution of (±) methyl5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}benzoate(intermediate 1-31; 500 mg, 1.56 mmol) in THF (10 mL) was treated with1-isothiocyanato-4-(propan-2-yloxy)benzene (1.00 eq., 302 mg, 1.56 mmol)and stirred at rt for 3 hours. EDC (2.00 eq., 598 mg, 3.12 mmol) wasadded, the reaction mixture heated to 70° C. and stirring at thistemperature continued for 3 days. The mixture was cooled to rt andpoured into an aqueous sodium hydrogen carbonate solution (10%). Theaqueous layer was extracted with ethyl acetate, the combined organiclayers washed with saturated ammonium chloride solution and brine, driedover sodium sulfate and concentrated in vacuo. The obtained material waspurified by flash chromatography (SiO₂-hexane/ethyl acetate) to give thetitle compound (565 mg, 72%) as racemic cis diastereomer.

UPLC-MS (ESI+): [M+H]⁺=480; R_(t)=1.54 min (Method F).

Example 2-158 (−) methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate

In analogy to reference example 2-150: A solution of (±) methyl3-(5-amino-2-methyl-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate(intermediate 1-33; 335 mg, 0.705 mmol) in THF (8 mL) was treated with1-isothiocyanato-4-(trifluoromethoxy)benzene (CAS No. [64285-95-6]; 1.00eq., 155 mg, 0.705 mmol) and stirred at rt for 2 hours. EDC (2.00 eq.,270 mg, 1.41 mmol) was added, the reaction mixture heated to 70° C. andstirring at this temperature continued for 24 hours. The mixture wascooled to rt and poured into an aqueous sodium hydrogen carbonatesolution (10%). The aqueous layer was extracted with ethyl acetate, thecombined organic layers washed with saturated ammonium chloride solutionand brine, dried over sodium sulfate and concentrated in vacuo. Theobtained material was purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the title compound (170 mg, 47%) asracemic cis diastereomer.

UPLC-MS (ESI+): [M+H]⁺=518; R_(t)=1.68 min (Method F).

Another batch of (±) methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoatewas additionally characterized by ¹H-NMR: ¹H-NMR (400 MHz, DMSO-d₆): δ[ppm]=0.96-0.98 (m, 6H), 1.03 (s, 3H), 1.10 (t, 1H), 1.36-1.41 (m, 2H),1.72-1.90 (m, 3H), 2.04 (t, 1H), 2.36 (s, 3H), 2.58-2.61 (m, 2H),2.84-2.88 (m, 2H), 3.60 (s, 3H), 4.55-4.61 (m, 1H), 7.16 (s, 1H),7.28-7.31 (m, 3H), 7.74-7.78 (m, 2H), 8.92 (br. s., 1H).

The enantiomers of the racemic material of example 2-158 were separatedby chiral preparative HPLC (System: Sepiatec: Prep SFC100; Column:Chiralpak IA 5 μm 250×20 mm; Solvent: CO₂/2-propanol 77/23; Flow: 80mL/min; Pressure(outlet): 150 bar; Temperature: 40° C.; Solution: 170mg/2 mL dichloromethane/methanol 1:1; Injection: 5×0.4 mL; Detection: UV254 nm) and analytically characterized by chiral HPLC (System: Agilent:1260 AS, MWD, Aurora SFC-Module; Column: Chiralpak IA 5 μm 100×4.6 mm;Solvent: CO₂/2-propanol 77/23; Flow: 4.0 mL/min; Pressure(outlet): 100bar; Temperature: 37.5° C.; Solution: 1.0 mg/mL EtOH/MeOH; Injection:10.0 μl; Detection: DAD 254 nm):

Example 2-158-1 methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A

R_(t)=1.79 min.

Another batch of methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A was additionally characterized by specific opticalrotation: [α]_(D) ²⁰=13.6°+/−0.10° (C=1.0000 g/100 mL, methanol).

Example 2-158-2 methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B

R_(t)=2.82 min.

Another batch of methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B was additionally characterized by specific optical rotation[α]_(D) ²⁰=−14.0°+/−0.12° (C=1.0000 g/100 mL, methanol).

The examples in Table 8 were prepared in an analogous manner to example2-158, starting from (±) methyl3-(5-amino-2-methyl-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate(intermediate 1-33) and the corresponding commercially availablethioisocyanates. The enantiomers were separated and analyzed accordingto the given procedures.

TABLE 8 Example/ Name of isothiocya- nate used Structure/Name Analyticaldata 2-159 1- isothiocya- nato-4- (propan- 2- yloxy)ben- zene

 

  (±) methyl 3-(6-methyl-2-{[4- (propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoate¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.96-0.98 (m, 6H), 1.04- 1.11 (m,4H), 1.25 (d, 6H), 1.36- 1.40 (m, 2H), 1.69-1.87 (m, 3H), 2.04 (t, 1H),2.34 (s, 3H), 2.56- 2.60 (m, 2H), 2.83-2.87 (m, 2H), 3.60 (s, 3H),4.46-4.59 (m, 2H), 6.85-6.89 (m, 2H), 7.08 (s, 1H), 7.23 (br. s., 1H),7.52-7.56 (m, 2H), 8.46 (br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 492;R_(t) = 1.65 min (Method F). 2-159-1 methyl 3-(6-methyl-2-{[4-(propan-2-Separation: yloxy)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep1200, trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)propanoate, FC; Column: Chiralpak IF 5 μm enantiomer A250 × 20 mm; Solvent: hexane/2- propanol 65:35 (v/v) +0.1% diethylamine;Flow: 25 mL/min; Temperature: rt; Solution: 260 mg/ 2 mL DCM/MeOH 1:1;Injection: 14 × 0,15 mL; Detection: UV 254 nm; Analysis: System: Agilent1260/Agilent 1290; Column: Chiralpak IF 3 μm 100 × 4.6 mm; Solvent:hexane/2- propanol 65:35 (v/v) +0.1% diethylamine; Flow: 1.0 mL/min;Temperature: 25° C.; Solution: 1.0 mg/mL EtOH/MeOH 1:1; Injection: 5.0μl; Detection: DAD 254 nm: R_(t) = 4.56 min. 2-159-2 methyl3-(6-methyl-2-{[4-(propan-2- R_(t) = 5.45 min.yloxy)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate, enantiomer B 2-160 1- isothiocya- nato-4-(propan- 2- yl)benzene

 

  (±) methyl 3-(6-methyl-2-{[4- (propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoate¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.95-0.97 (m, 6H), 1.01 (s, 3H),1.07 (t, 1H), 1.19 (d, 6H), 1.34-1.39 (m, 2H), 1.69-1.89 (m, 3H), 2.02(t, 1H), 2.34 (s, 3H), 2.56-2.60 (m, 2H), 2.77-2.86 (m, 3H), 3.59 (s,3H), 4.51-4.59 (m, 1H), 7.10 (s, 1H), 7.13-7.15 (m, 2H), 7.25 (s, 1H),7.52-7.54 (m, 2H), 8.55 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 476; R_(t) =1.72 min (Method F). 2-160-1 methyl 3-(6-methyl-2-{[4-(propan-2-Separation: yl)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep 1200,trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)propanoate, FC; Column: Chiralpak IA 5 μm enantiomer A250 × 20 mm; Solvent: hexane/2- propanol 80:20 (v/v); Flow: 15 mL/min;Temperature: rt; Solution: 222 mg/3 mL DCM/MeOH 1:1; Injection: 6 × 0,5mL; Detection: UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290;Column: Chiralpak IA 3 μm 100 × 4.6 mm; Solvent: hexane/2- propanol80:20 (v/v); Flow: 1.0 mL/min; Temperature: 25° C.; Solution: 1.0 mg/mLEtOH/MeOH 1:1; Injection: 5.0 μl; Detection: DAD 254 nm: R_(t) = 4.93min. 2-160-2 methyl 3-(6-methyl-2-{[4-(propan-2- R_(t) = 8.64 min.yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate, enantiomer B 2-161 1- isothiocya- nato-4-(trifluoro- methyl)ben- zene

 

  (±) methyl 3-(6-methyl-2-{[4- (trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoate¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.96-0.98 (m, 6H), 1.02 (s, 3H),1.10 (t, 1H), 1.37-1.41 (m, 2H), 1.73-1.90 (m, 3H), 2.04 (t, 1H), 2.37(s, 3H), 2.59-2.63 (m, 2H), 2.86-2.90 (m, 2H), 3.60 (s, 3H), 4.57-4.65(m, 1H), 7.21 (s, 1H), 7.35 (s, 1H), 7.62-7.64 (m, 2H), 7.82-7.84 (m,2H), 9.17 (br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 502; R_(t) = 1.65 min(Method D). 2-161-1 methyl 3-(6-methyl-2-{[4- Separation:(trifluoromethyl)phenyl]amino}-1- System: Agilent: Prep 1200,[(cis)-3,3,5-trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)propanoate, FC; Column: Chiralpak IA 5 μm enantiomer A250 × 20 mm; Solvent: hexane/2- propanol 80:20 (v/v); Flow: 15 mL/min;Temperature: rt; Solution: 300 mg/4 mL DCM/MeOH 1:1; Injection: 20 × 0.2mL; Detection: UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290;Column: Chiralpak IA 3 μm 100 × 4.6 mm; Solvent: hexane/2- propanol75:25 (v/v); Flow: 1.0 mL/min; Temperature: 25° C.; Solution: 1.0 mg/mLEtOH/MeOH 1:1; Injection: 5.0 μl; Detection: DAD 254 nm: R_(t) = 5.38min. 2-161-2 methyl 3-(6-methyl-2-{[4- R_(t) = 8.00 min.(trifluoromethyl)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate, enantiomer B

Example 2-162 (±)3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid

In analogy to reference example 2-26: (±) Methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate(example 2-158; 47 mg, 0.091 mmol) was reacted with lithium hydroxide(5.0 eq., 11 mg, 0.45 mmol) in a mixture of THF/water (1:1, 2 mL) at 70°C. overnight to give the title compound (45 mg, 93%) which was notfurther purified.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97 (d, 3H), 1.02 (s, 3H), 1.06 (s,3H), 1.18 (t, 1H), 1.37-1.40 (m, 1H), 1.57-1.60 (m, 1H), 1.72-1.81 (m,1H), 1.93-1.96 (m, 2H), 2.10 (t, 1H), 2.41 (s, 3H), 2.50-2.53 (m, 2H),2.85-2.89 (m, 2H), 4.78-4.84 (m, 1H), 7.18 (s, 1H), 7.49-7.51 (m, 2H),7.62-7.65 (m, 3H), 10.91 (br. s., 0.7H*), 12.12 (br. s., 0.8H*), 13.03(br. s., 0.5H*).

UPLC-MS (ESI+): [M+H]⁺=504; R_(t)=1.00 min (Method F).

Example 2-162-13-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer A

In analogy to reference example 2-26: Methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A (example 2-158-1; 33 mg, 0.064 mmol) was reacted withlithium hydroxide (5.0 eq., 7.6 mg, 0.32 mmol) in a mixture of THF/water(1:1, 2 mL) at 70° C. overnight to give the title compound (40 mg,quant.) which was not further purified.

¹H-NMR (300 MHz, DMSO-d₆): 5 [ppm]=0.97 (d, 3H), 1.02 (s, 3H), 1.06 (s,3H), 1.18 (t, 1H), 1.36-1.40 (m, 1H), 1.57-1.61 (m, 1H), 1.74-1.82 (m,1H), 1.94-1.98 (m, 2H), 2.10 (t, 1H), 2.41 (s, 3H), 2.50-2.53 (m, 2H),2.84-2.89 (m, 2H), 4.80-4.89 (m, 1H), 7.18 (s, 1H), 7.48-7.51 (m, 2H),7.63-7.66 (m, 3H), 11.02 (br. s., 0.7H*), 12.17 (br. s., 0.7H*), 13.04(br. s., 0.6H*).

UPLC-MS (ESI+): [M+H]⁺=504; R_(t)=1.02 min (Method F).

Specific optical rotation: [c]_(D) ²⁰=30.90+/−0.48° (C=1.0000 g/100 mL,methanol).

Example 2-162-23-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer B

In analogy to reference example 2-26: Methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B (example 2-158-2; 30 mg, 0.058 mmol) was reacted withlithium hydroxide (5.0 eq., 6.9 mg, 0.29 mmol) in a mixture of THF/water(1:1, 2 mL) at 70° C. overnight to give the title compound (38 mg,quant.) which was not further purified.

¹H-NMR (300 MHz, DMSO-d₆): δ [ppm]=0.97 (d, 3H), 1.02 (s, 3H), 1.06 (s,3H), 1.18 (t, 1H), 1.36-1.40 (m, 1H), 1.57-1.61 (m, 1H), 1.74-1.83 (m,1H), 1.94-1.97 (m, 2H), 2.10 (t, 1H), 2.41 (s, 3H), 2.50-2.53 (m, 2H),2.85-2.90 (m, 2H), 4.80-4.88 (m, 1H), 7.18 (s, 1H), 7.49-7.52 (m, 2H),7.62-7.65 (m, 3H), 11.02 (br. s., 0.8H*), 12.16 (br. s., 0.6H*), 13.04(br. s., 0.6H*).

UPLC-MS (ESI+): [M+H]⁺=504; R_(t)=1.00 min (Method F).

Specific optical rotation: [α]_(D) ²⁰=−28.3°+/−0.89° (C=1.0000 g/100 mL,methanol).

The examples in Table 9 were prepared in an analogous manner to example2-162, starting from the given ester precursors. The example 2-165 waspurified by preparative HPLC.

TABLE 9 Ester Example Structure/Name Analytical data precursor 2-163

 

  (±) 3-(6-methyl-2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoic acid ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.98 (d, 3H), 1.03 (s, 3H), 1.07 (s, 3H),1.31 (d, 6H), 1.36-1.40 (m, 1H), 1.58-1.60 (m, 1H), 1.71-1.80 (m, 2H),1.85- 1.95 (m, 2H), 2.12 (t, 1H), 2.40 (s, 3H), 2.83-2.87 (m, 2H),4.63-4.76 (m, 2H), 7.05-7.08 (m, 2H), 7.11 (s, 1H), 7.36-7.40 (m, 2H),7.61 (s, 1H), 10.53 (br. s., 1H), 12.17 (br. s., 1H). UPLC-MS (ESI+):[M + H]⁺ = 478; R_(t) = 0.94 min (Method F). Example 2-159 2-163-13-(6-methyl-2-{[4-(propan-2- ¹H-NMR (400 MHz, DMSO- Exampleyloxy)phenyl]amino}-1-[(cis)- d₆): δ [ppm] = 0.98 (d, 3H), 2-159-13,3,5-trimethylcyclohexyl]-1H- 1.03 (s, 3H), 1.07 (s, 3H),benzimidazol-5-yl)propanoic 1.31 (d, 6H), 1.37-1.40 (m, acid, enantiomerA 1H), 1.58-1.61 (m, 1H), 1.72-1.80 (m, 2H), 1.84- 1.95 (m, 2H), 2.12(t, 1H), 2.40 (s, 3H), 2.83-2.87 (m, 2H), 4.63-4.76 (m, 2H), 7.05-7.09(m, 2H), 7.11 (s, 1H), 7.36-7.40 (m, 2H), 7.60 (s, 1H), 10.52 (br. s.,1H), 12.16 (br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 478; R_(t) = 1.00min (Method B). Specific optical rotation: [α]_(D) ²⁰ = 48.8° +/− 0.39°(C = 1.0000 g/100 mL, methanol). 2-163-2 3-(6-methyl-2-{[4-(propan-2-¹H-NMR (400 MHz, DMSO- Example yloxy)phenyl]amino}-1-[(cis)- d₆): δ[ppm] = 0.98 (d, 3H), 2-159-2 3,3,5-trimethylcyclohexyl]-1H- 1.03 (s,3H), 1.07 (s, 3H), benzimidazol-5-yl)propanoic 1.31 (d, 6H), 1.37-1.40(m, acid, enantiomer B 1H), 1.58-1.61 (m, 1H), 1.71-1.80 (m, 2H), 1.84-1.96 (m, 2H), 2.12 (t, 1H), 2.40 (s, 3H), 2.83-2.89 (m, 2H), 4.63-4.77(m, 2H), 7.05-7.09 (m, 2H), 7.11 (s, 1H), 7.36-7.40 (m, 2H), 7.60 (s,1H), 10.53 (br. s., 1H), 12.18 (br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ =478; R_(t) = 1.00 min (Method B). Specific optical rotation: [α]_(D) ²⁰= −51.6° +/− 0.34° (C = 1.0000 g/100 mL, methanol). 2-164

 

  (±) 3-(6-methyl-2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoic acid ¹H-NMR (400MHz, DMSO- d₆): δ [ppm] = 0.97 (d, 3H), 1.02 (s, 3H), 1.06 (s, 3H),1.15-1.18 (m, 1H), 1.25 (d, 6H), 1.36-1.39 (m, 1H), 1.56-1.59 (m, 1H),1.72- 1.81 (m, 1H), 1.92-1.95 (m, 2H), 2.11 (t, 1H), 2.41 (s, 3H),2.84-2.88 (m, 2H), 2.92-2.99 (m, 1H), 4.76- 4.82 (m, 1H), 7.15 (s, 1H),7.37-7.42 (m, 4H), 7.61 (br. s., 1H), 10.74 (br. s., 0.7H*), 12.17 (br.s., 1H), 12.77 (br. s., 0.8H*). UPLC-MS (ESI+): [M + H]⁺ = 462; R_(t) =1.00 min (Method F). Example 2-160 2-164-1 3-(6-methyl-2-{[4-(propan-2-¹H-NMR (400 MHz, DMSO- Example yl)phenyl]amino}-1-[(cis)-3,3,5- d₆): δ[ppm] = 0.98 (d, 3H), 2-160-1 trimethylcyclohexyl]-1H- 1.02 (s, 3H),1.05 (s, 3H), benzimidazol-5-yl)propanoic 1.15-1.19 (m, 1H), 1.25 (d,acid, enantiomer A 6H), 1.37-1.40 (m, 1H), 1.56-1.59 (m, 1H), 1.72- 1.81(m, 1H), 1.84-1.95 (m, 2H), 2.11 (t, 1H), 2.41 (s, 3H), 2.84-2.88 (m,2H), 2.96 (sept, 1H), 4.68-4.76 (m, 1H), 7.15 (s, 1H), 7.39 (br. s.,4H), 7.62 (br. s., 1H), 10.54 (br. s., 0.7H*), 12.18 (br. s., 1H), 12.76(br. s., 0.8H*). Specific optical rotation: [α]_(D) ²⁰ = 35.3° +/− 0.15°(C = 1.0000 g/100 mL, methanol). 2-164-2 3-(6-methyl-2-{[4-(propan-2-¹H-NMR (400 MHz, DMSO- Example yl)phenyl]amino}-1-[(cis)-3,3,5- d₆): δ[ppm] = 0.98 (d, 3H), 2-160-2 trimethylcyclohexyl]-1H- 1.02 (s, 3H),1.05 (s, 3H), benzimidazol-5-yl)propanoic 1.15-1.18 (m, 1H), 1.24 (d,acid, enantiomer B 6H), 1.37-1.40 (m, 1H), 1.56-1.58 (m, 1H), 1.72- 1.81(m, 1H), 1.84-1.95 (m, 2H), 2.11 (t, 1H), 2.40 (s, 3H), 2.84-2.88 (m,2H), 2.95 (sept, 1H), 4.65-4.72 (m, 1H), 7.15 (s, 1H), 7.39 (br. s.,4H), 7.61 (br. s., 1H), 10.45 (br. s., 0.7H*), 12.17 (br. s., 1H), 12.76(br. s., 0.8H*). Specific optical rotation: [α]_(D) ²⁰ = −34.4° +/−0.17° (C = 1.0000 g/100 mL, methanol). 2-165

 

  (±) 3-(6-methyl-2-{[4- (trifluoromethyl)phenyl]amino}- 1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoic acid 1H-NMR (400MHz, DMSO- d₆): δ [ppm] = 0.96-0.98 (m, 6H), 1.02 (s, 3H), 1.10 (t, 1H),1.37-1.40 (m, 2H), 1.73-1.91 (m, 3H), 2.05 (t, 1H), 2.37 (s, 3H),2.83-2.86 (m, 2H), 4.58-4.64 (m, 1H), 7.21 (s, 1H), 7.35 (s, 1H),7.62-7.64 (m, 2H), 7.82- 7.84 (m, 2H), 9.17 (br. s., IH), 12.06 (br. s.,1H). UPLC-MS (ESI+): [M + H]⁺ = 488; R_(t) = 0.95 min (Method B).Example 2-161

Example 2-165-13-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer A

A solution of methyl3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A (example 2-161-1; 100 mg, 0.199 mmol) in pyridine (4 mL)was treated with lithium iodide (5.00 eq., 133 mg, 0.997 mmol) andheated to 125° C. for 3 days. The mixture was cooled to rt andconcentrated under reduced pressure. The residue was taken up with 2Naq. HCl and extracted with ethyl acetate, the combined organic layerswere dried over sodium sulfate and concentrated in vacuo. The obtainedmaterial was purified by preparative HPLC to give the title compound (8mg, 7%).

UPLC-MS (ESI+): [M+H]⁺=488; R_(t)=0.97 min (Method F).

Example 2-165-23-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer B

In analogy to example 2-165-1: Methyl3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B (example 2-161-2; 74 mg, 0.15 mmol) was reacted withlithium iodide (5.0 eq., 99 mg, 0.74 mmol) in pyridine (3 mL) at 125° C.for 3 days to give after preparative HPLC the title compound (45 mg,53%).

UPLC-MS (ESI+): [M+H]⁺=488; R_(t)=0.97 min (Method F).

Example 2-166 (±) methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate

In analogy to reference example 2-150: A solution of (±) methyl3-(5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate(intermediate 1-32; 1.40 g, 3.62 mmol) in THF (39 mL) was treated with1-isothiocyanato-4-(trifluoromethoxy)benzene (CAS No. [64285-95-6]; 1.00eq., 792 mg, 3.62 mmol) and stirred at rt for 3 hours. EDC (2.00 eq.,1.39 g, 7.23 mmol) was added, the reaction mixture heated to 70° C. andstirring at this temperature continued for 24 hours. The mixture wascooled to rt and poured into an aqueous sodium hydrogen carbonatesolution (10%). The aqueous layer was extracted with ethyl acetate, thecombined organic layers washed with saturated ammonium chloride solutionand brine, dried over sodium sulfate and concentrated in vacuo. Theobtained material was purified by flash chromatography(SiO₂-hexane/ethyl acetate) to give the title compound (1.58 g, 80%) asracemic cis diastereomer.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.97-0.98 (m, 6H), 1.02 (s, 3H), 1.08(t, 1H), 1.38-1.41 (m, 2H), 1.72-1.91 (m, 3H), 2.02 (t, 1H), 2.55-2.59(m, 2H), 2.83-2.87 (m, 2H), 3.58 (s, 3H), 3.84 (s, 3H), 4.55-4.63 (m,1H), 6.97 (s, 1H), 7.17 (s, 1H), 7.27-7.29 (m, 2H), 7.67-7.71 (m, 2H),8.87 (br. s., 1H).

UPLC-MS (ESI+): [M+H]⁺=534; R_(t)=1.67 min (Method F).

The enantiomers of the racemic material of example 2-166 were separatedby chiral preparative HPLC (System: 2× Labomatic Pump HD-3000, LabomaticAS-3000, Knauer DAD 2600, Labomatic Labcol Vario 4000 Plus; Column:Chiralpak ID 5 μm 250×30 mm Nr.:018 BF; Solvent:hexane/2-propanol/diethylamine 70:30:0.1 (v/v/v); Flow: 50 mL/min;Temperature: rt; Solution: 1400 mg/9.5 mL DCM/MeOH; Injection: 7×1.5 mL;Detection: UV 254 nm) and analytically characterized by chiral HPLC(System: Agilent 1260; Column: Chiralpak ID 5 μm 150×4.6 mm; Solvent:hexane/2-propanol/diethylamine 70:30:0.1 (v/v/v); Flow: 1.0 mL/min;Temperature: 25° C.; Solution: 1.0 mg/mL EtOH/MeOH 2:1; Injection: 5.0μl; Detection: DAD 254 nm) and specific optical rotation:

Example 2-166-1 methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A

R_(t)=4.09 min; [α]_(D) ²⁰=14.3°+/−0.32° (C=1.0000 g/100 mL, methanol).

Example 2-166-2 methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B

R_(t)=5.94 min; [α]_(D) ²⁰=−14.0°+/−2.10° (C=1.0000 g/100 mL, methanol).

The examples in Table 10 were prepared in an analogous manner to example2-166, starting from (±) methyl3-(5-amino-2-methoxy-4-{[(cis)-3,3,5-trimethylcyclohexyl]amino}phenyl)propanoate(intermediate 1-32) and the corresponding commercially availablethioisocyanates. The enantiomers were separated and analyzed accordingto the given procedures.

TABLE 10 Example/ Name of isothiocya- nate used Structure/NameAnalytical data 2-176

 

  (±) methyl 3-{2-[(4- isopropoxyphenyl)amino]-6-methoxy-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoate ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.96-0.99 (m, 6H), 1.03- 1.10 (m, 4H), 1.25 (d, 6H), 1.37- 1.41 (m, 2H),1.69-1.90 (m, 3H), 2.02 (t, 1H), 2.54-2.57 (m, 2H), 2.81-2.85 (m, 2H),3.58 (s, 3H), 3.83 (s, 3H), 4.46-4.60 (m, 2H), 6.84-6.88 (m, 2H), 6.92(s, 1H), 7.09 (s, 1H), 7.49-7.53 (m, 2H), 8.42 (br. s., 1H). UPLC-MS(ESI+): [M + H]⁺ = 508; R_(t) = 1.59 min (Method D). 2-176-1 methyl3-{2-[(4- Separation: isopropoxyphenyl)amino]-6- System: LabomaticHD3000, AS- methoxy-1-[(cis)-3,3,5- 3000, Labcol Vario 4000 Plus,trimethylcyclohexyl]-1H- Knauer DAD 2600; Column:benzimidazol-5-yl}propanoate, Chiralpak IA 5 μ 250 × 30 mm; Eluentenantiomer A A: hexane + 0.1% vol. diethylamine (99%), Eluent B:ethanol; isocratic: 70% A + 30% B; Flow: 40.0 ml/min; Temperature: rt;Solution: 220 mg/4 mL DCM/MeOH; Injection: 4 × 1 mL; Detection: DAD 254nm; Analysis: System: Agilent HPLC 1260|Column: Chiralpak IA 3 μ 100 ×4.6 mm; Eluent A: hexane + 0.1% vol. diethylamine (99%), Eluent B:ethanol; isocratic: 70% A + 30% B; Flow: 1.0 ml/min; Temperature: 25°C.; Solution: 1.0 mg/mL EtOH/MeOH 1:1; Injection: 5 μl; Detection: DAD280 nm: R_(t) = 4.79 min. 2-176-2 methyl 3-{2-[(4- R_(t) = 5.78 min.isopropoxyphenyl)amino]-6- methoxy-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl}propanoate, enantiomer B2-167 1- isothiocya- nato-4- (propan- 2- yl)benzene

 

  (±) (±) methyl 3-(6-methoxy-2-{[4- (propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoate¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.96-1.10 (m, 10H), 1.19 (d, 6H),1.37-1.40 (m, 2H), 1.70- 1.88 (m, 3H), 2.01 (t, 1H), 2.54- 2.58 (m, 2H),2.80-2.86 (m, 3H), 3.58 (s, 3H), 3.83 (s, 3H), 4.55- 4.61 (m, 1H), 6.94(s, 1H), 7.12- 7.15 (m, 3H), 7.48-7.50 (m, 2H), 8.52 (br. s., 1H).UPLC-MS (ESI+): [M + H]⁺ = 492; R_(t) = 1.70 min (Method B). 2-167-1methyl 3-(6-methoxy-2-{[4-(propan- Separation:2-yl)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep 1200,trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)propanoate, FC; Column: Chiralpak IC 5 μm enantiomer A250 × 20 mm; Solvent: hexane/ ethanol 80:20 (v/v); Flow: 15 mL/min;Temperature: rt; Solution: 188 mg/2 mL DCM/MeOH 1:1; Injection: 7 × 0,3mL; Detection: UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290;Column: Chiralpak IC 3 μm 100 × 4.6 mm; Solvent: hexane/ ethanol 80:20(v/v); Flow: 1.0 mL/min; Temperature: 25° C.; Solution: 1.0 mg/mLEtOH/MeOH 1:1; Injection: 5.0 μl; Detection: DAD 254 nm: R_(t) = 3.12min. 2-167-2 methyl 3-(6-methoxy-2-{[4-(propan- R_(t) = 4.43 min.2-yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate, enantiomer B 2-168 1- isothiocya- nato-4-(trifluoro- methyl)ben- zene

 

  (±) methyl 3-(6-methoxy-2-{[4- (trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoate¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.96-1.11 (m, 10H), 1.38- 1.41 (m,2H), 1.72-1.86 (m, 3H), 2.02 (t, 1H), 2.56-2.59 (m, 2H), 2.84-2.88 (m,2H), 3.59 (s, 3H), 3.85 (s, 3H), 4.57-4.65 (m, 1H), 6.99 (s, 1H), 7.22(s, 1H), 7.61-7.63 (m, 2H), 7.74-7.76 (m, 2H), 9.13 (br. s., 1H).UPLC-MS (ESI+): [M + H]⁺ = 518; R_(t) = 1.64 min (Method B). 2-168-1methyl 3-(6-methoxy-2-{[4- Separation: (trifluoromethyl)phenyl]amino}-1-System: Agilent: Prep 1200, [(cis)-3,3,5-trimethylcyclohexyl]-1H- 2 ×Prep Pump, DLA, MWD, Prep benzimidazol-5-yl)propanoate, FC; Column:Chiralpak IE 5 μm enantiomer A 250 × 20 mm; Solvent: hexane/2- propanol69:31 (v/v) + 0.1% diethylamine; Flow: 15 mL/min; Temperature: rt;Solution: 298 mg/ 3 mL DCM/MeOH 1:1; Injection: 21 × 0,15 mL; Detection:UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290; Column:Chiralpak IE 3 μm 100 × 4.6 mm; Solvent: hexane/2- propanol 69:31(v/v) + 0.1% diethylamine; Flow: 1.0 mL/min; Temperature: 25° C.;Solution: 1.0 mg/mL EtOH/MeOH 1:1; Injection: 5.0 μl; Detection: DAD 254nm: R_(t) = 3.70 min. Specific optical rotation: [α]_(D) ²⁰ = 14.7° +/−0.98° (C = 1.0000 g/100 mL, methanol). 2-168-2 methyl3-(6-methoxy-2-{[4- R_(t) = 5.14 min. Specific optical(trifluoromethyl)phenyl]amino}-1- rotation: [α]_(D) ²⁰ = −16.6° +/−1.49° (C = [(cis)-3,3,5-trimethylcyclohexyl]-1H- 1.0000 g/100 mL,methanol). benzimidazol-5-yl)propanoate, enantiomer B

Example 2-169 (±)3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoicacid

In analogy to reference example 2-26: (±) Methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate(example 2-166; 39 mg, 0.073 mmol) was reacted with lithium hydroxide(5.0 eq., 8.8 mg, 0.37 mmol) in a mixture of THF/water (1:1, 2 mL) at70° C. overnight to give the title compound (44 mg, quant.) which wasnot further purified.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.98 (d, 3H), 1.01 (s, 3H), 1.05 (s,3H), 1.13 (t, 1H), 1.37-1.41 (m, 1H), 1.52-1.56 (m, 1H), 1.72-1.81 (m,1H), 1.92-1.95 (m, 2H), 2.06 (t, 1H), 2.46-2.50 (m, 2H), 2.81-2.85 (m,2H), 3.89 (s, 3H), 4.74-4.80 (m, 1H), 7.08 (br. s., 1H), 7.19 (s, 1H),7.40-7.42 (m, 2H), 7.64-7.66 (m, 2H), 12.09 (br. s., 1H).

UPLC-MS (ESI+): [M+H]⁺=520; R_(t)=1.01 min (Method D).

Example 2-169-13-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer A

In analogy to reference example 2-26: Methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A (example 2-166-1; 39 mg, 0.073 mmol) was reacted withlithium hydroxide (5.0 eq., 8.8 mg, 0.37 mmol) in a mixture of THF/water(1:1, 2 mL) at 70° C. overnight to give the title compound (38 mg, 95%)which was not further purified.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.98 (d, 3H), 1.02 (s, 3H), 1.06 (s,3H), 1.17 (t, 1H), 1.37-1.40 (m, 1H), 1.61-1.63 (m, 1H), 1.73-1.82 (m,1H), 1.92-1.97 (m, 2H), 2.08 (t, 1H), 2.46-2.50 (m, 2H), 2.83-2.86 (m,2H), 3.92 (s, 3H), 4.78-4.84 (m, 1H), 7.15 (br. s., 1H), 7.20 (s, 1H),7.48-7.50 (m, 2H), 7.61-7.63 (m, 2H), 10.78 (br. s., 0.6H*), 12.12 (br.s., 0.7H*), 13.11 (br. s., 0.5H*).

UPLC-MS (ESI+): [M+H]⁺=520; R_(t)=0.98 min (Method F).

Specific optical rotation: [α]_(D) ²⁰=32.7°+/−0.34° (C=1.0000 g/100 mL,methanol).

Example 2-169-23-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer B

In analogy to reference example 2-26: Methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B (example 2-166-2; 76 mg, 0.14 mmol) was reacted withlithium hydroxide (5.0 eq., 17 mg, 0.71 mmol) in a mixture of THF/water(1:1, 3.5 mL) at 70° C. overnight to give the title compound (78 mg,quant.) which was not further purified.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.98 (d, 3H), 1.02 (s, 3H), 1.06 (s,3H), 1.16 (t, 1H), 1.37-1.41 (m, 1H), 1.60-1.63 (m, 1H), 1.73-1.82 (m,1H), 1.92-1.96 (m, 2H), 2.07 (t, 1H), 2.46-2.54 (m, 2H), 2.83-2.86 (m,2H), 3.91 (s, 3H), 4.76-4.83 (m, 1H), 7.14 (br. s., 1H), 7.20 (s, 1H),7.48-7.50 (m, 2H), 7.61-7.63 (m, 2H), 10.69 (br. s., 0.7H*), 12.12 (br.s., 0.8H*), 13.09 (br. s., 0.5H*).

UPLC-MS (ESI+): [M+H]⁺=520; R_(t)=0.95 min.

Specific optical rotation: [α]_(D) ²⁰=−31.4°+/−0.17° (C=1.0000 g/100 mL,methanol).

The examples in Table 11 were prepared in an analogous manner to example2-169, starting from the given ester precursors. The example 2-171 waspurified by preparative HPLC giving example 2-171 along with example2-178.

TABLE 11 Ester Example Structure/Name Analytical data precursor 2-177

 

  (±) 3-{2-[(4- isopropoxyphenyl)amino]-6- methoxy-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl}propanoic acid ¹H-NMR (400MHz, DMSO- d₆): δ [ppm] = 0.98 (d, 3H), 1.03 (s, 3H), 1.08 (s, 3H),1.14-1.20 (m, 1H), 1.31 (d, 6H), 1.37-1.40 (m, 1H), 1.61-1.64 (m, 1H),1.72- 1.80 (m, 1H), 1.88-1.99 (m, 2H), 2.09 (t, 1H), 2.45-2.50 (m, 2H),2.80-2.84 (m, 2H), 3.91 (s, 3H), 4.66 (sept, 1H), 4.73-4.80 (m, 1H),7.05- 7.07 (m, 2H), 7.13 (s, 2H), 7.37-7.39 (m, 2H), 10.51 (br. s., 1H),12.50 (br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 494; R_(t) = 0.89 min(Method D). 2-176 2-177-1 3-{2-[(4- UPLC-MS (ESI+): [M + H]⁺ = 2-176-1isopropoxyphenyl)amino]-6- 494; R_(t) = 0.93 min (Methodmethoxy-1-[(cis)-3,3,5- F). trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoic acid, enantiomer A 2-177-2 3-{2-[(4- UPLC-MS(ESI+): [M + H]⁺ = 2-176-2 isopropoxyphenyl)amino]-6- 494; R_(t) = 0.94min (Method methoxy-1-[(cis)-3,3,5- F). trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoic acid, enantiomer B 2-170

 

  (±) 3-(6-methoxy-2-{[4-(propan- 2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoic acid ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.99 (d, 3H), 1.03 (s, 3H), 1.06 (s, 3H),1.17 (t, 1H), 1.25 (d, 6H), 1.37-1.41 (m, 1H), 1.60- 1.63 (m, 1H),1.73-1.82 (m, 1H), 1.86-1.99 (m, 2H), 2.08 (t, 1H), 2.45-2.50 (m, 2H),2.82-2.85 (m, 2H), 2.91-3.01 (m, 1H), 3.91 (s, 3H), 4.72-4.79 (m, 1H),7.14 (s, 1H), 7.17 (s, 1H), 7.39 (br. s., 4H), 10.48 (br. s., 0.7H*),12.10 (br. s., 0.9H*), 12.77 (br. s., 0.7H*). UPLC-MS (ESI+): [M + H]⁺ =478; R_(t) = 1.05 min (Method B). Example 2-167 2-170-13-(6-methoxy-2-{[4-(propan-2- ¹H-NMR (400 MHz, DMSO- 2-167-1yl)phenyl]amino}-1-[(cis)-3,3,5- d₆): δ [ppm] = 0.99 (d, 3H),trimethylcyclohexyl]-1H- 1.03 (s, 3H), 1.06 (s, 3H),benzimidazol-5-yl)propanoic 1.16 (t, 1H), 1.24 (d, 6H), acid, enantiomerA 1.37-1.40 (m, 1H), 1.59- 1.62 (m, 1H), 1.73-1.81 (m, 1H), 1.87-1.99(m, 2H), 2.08 (t, 1H), 2.45-2.50 (m, 2H), 2.82-2.85 (m, 2H), 2.95 (sept,1H), 3.91 (s, 3H), 4.74-4.82 (m, 1H), 7.13 (s, 1H), 7.17 (s, 1H),7.36-7.40 (m, 4H), 10.57 (br. s., 0.7H*), 12.10 (br. s., 0.9H*), 12.78(br. s., 0.7H*). UPLC-MS (ESI+): [M + H]⁺ = 478; R_(t) = 1.01 min(Method F). Specific optical rotation: [α]_(D) ²⁰ = 24.6° +/− 3.89° (C =1.0000 g/100 mL, methanol). 2-170-2 3-(6-methoxy-2-{[4-(propan-2- ¹H-NMR(400 MHz, DMSO- 2-167-2 yl)phenyl]amino}-1-[(cis)-3,3,5- d₆): δ [ppm] =0.99 (d, 3H), trimethylcyclohexyl]-1H- 1.03 (s, 3H), 1.06 (s, 3H),benzimidazol-5-yl)propanoic 1.16 (t, 1H), 1.24 (d, 6H), acid, enantiomerB 1.37-1.40 (m, 1H), 1.60- 1.63 (m, 1H), 1.73-1.82 (m, 1H), 1.87-1.99(m, 2H), 2.08 (t, 1H), 2.45-2.50 (m, 2H), 2.82-2.85 (m, 2H), 2.96 (sept,1H), 3.91 (s, 3H), 4.72-4.80 (m, 1H), 7.14 (s, 1H), 7.17 (s, 1H), 7.39(br. s., 4H), 10.50 (br. s., 0.6H*), 12.09 (br. s., 0.8H*), 12.77 (br.s., 0.7H*). UPLC-MS (ESI+): [M + H]⁺ = 478; R_(t) = 1.01 min (Method F).Specific optical rotation: [α]_(D) ²⁰ = −26.1° +/− 5.69° (C = 1.0000g/100 mL, methanol). 2-171

 

  (±) 3-(6-methoxy-2-{[4- (trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H- benzimidazol-5-yl)propanoicacid ¹H-NMR (400 MHz, DMSO- d₆): δ [ppm] = 0.97-0.98 (m, 6H), 1.02 (s,3H), 1.08 (t, 1H), 1.38-1.42 (m, 2H), 1.73-1.89 (m, 3H), 2.03 (t, 1H),2.43-2.47 (m, 2H), 2.80-2.84 (m, 2H), 3.85 (s, 3H), 4.58-4.64 (m, 1H),6.99 (s, 1H), 7.22 (s, 1H), 7.60-7.63 (m, 2H), 7.74- 7.76 (m, 2H), 9.15(br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 504; R_(t) = 1.00 min (MethodF). Example 2-168 2-178

 

  (±) 4-({5-(2-carboxyethyl)-6- methoxy-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-2- yl}amino)benzoic acid ¹H-NMR(400 MHz, DMSO- d₆): δ [ppm] = 0.96-0.98 (m, 6H), 1.01 (s, 3H), 1.07 (t,1H), 1.38-1.41 (m, 2H), 1.72-1.89 (m, 3H), 2.02 (t, 1H), 2.45-2.50 (m,2H), 2.80-2.84 (m, 2H), 3.85 (s, 3H), 4.57-4.65 (m, 1H), 6.97 (s, 1H),7.22 (s, 1H), 7.59-7.61 (m, 2H), 7.83- 7.85 (m, 2H), 9.04 (br. s., 1H).UPLC-MS (ESI+): [M + H]⁺ = 480; R_(t) = 0.66 min (Method F). 2-168

Example 2-171-13-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer A

In analogy to example 2-165-1: Methyl3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer A (example 2-168-1; 114 mg, 0.220 mmol) was reacted withlithium iodide (5.00 eq., 147 mg, 1.10 mmol) in pyridine (4 mL) at 125°C. for 3 days to give after preparative HPLC the title compound (34 mg,30%).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=0.97-0.98 (m, 6H), 1.02 (s, 3H), 1.08(t, 1H), 1.39-1.42 (m, 2H), 1.74-1.81 (m, 1H), 1.84-1.90 (m, 2H), 2.03(t, 1H), 2.47-2.50 (m, 2H), 2.81-2.84 (m, 2H), 3.85 (s, 3H), 4.58-4.64(m, 1H), 6.99 (s, 1H), 7.22 (s, 1H), 7.61-7.63 (m, 2H), 7.74-7.76 (m,2H), 9.12 (br. s., 1H), 12.07 (br. s., 1H).

UPLC-MS (ESI+): [M+H]⁺=504; R_(t)=0.96 min (Method F).

Example 2-171-23-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, enantiomer B

In analogy to example 2-165-1: Methyl3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate,enantiomer B (example 2-168-2; 122 mg, 0.236 mmol) was reacted withlithium iodide (5.00 eq., 158 mg, 1.18 mmol) in pyridine (4 mL) at 125°C. for 3 days to give after preparative HPLC the title compound (35 mg,29%).

¹H-NMR (500 MHz, DMSO-d₆): δ [ppm]=0.97-0.98 (m, 6H), 1.02 (s, 3H), 1.08(t, 1H), 1.39-1.41 (m, 2H), 1.74-1.81 (m, 1H), 1.84-1.90 (m, 2H), 2.03(t, 1H), 2.46-2.50 (m, 2H), 2.81-2.84 (m, 2H), 3.85 (s, 3H), 4.58-4.64(m, 1H), 6.99 (s, 1H), 7.22 (s, 1H), 7.61-7.63 (m, 2H), 7.74-7.76 (m,2H), 9.12 (br. s., 1H), 12.09 (br. s., 1H).

UPLC-MS (ESI+): [M+H]⁺=504; R_(t)=0.96 min (Method F).

Example 2-179 (±)2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}acetamide

(±)[(2-{[4-(Trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid (example 2-123, 80 mg, 0.16 mmol) was dissolved in DMF (1.5 mL);HATU (92 mg, 0.24 mmol), triethylamine (24 mg, 0.24 mmol) and3-(trifluoromethyl)-2-aminomethylpyridine (43 mg, 0.24 mmol) were added.After stirring overnight at rt the reaction mixture was subjected topreparative HPLC to yield the title compound.

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm]=0.92-1.15 (m, 10H), 1.34-1.45 (m,2H), 1.65-1.94 (m, 3H), 2.02 (t, 1H), 4.57 (s, 2H), 4.66 (d, 2H), 6.74(dd, 1H), 7.09 (d, 1H), 7.32 (d, 2H), 7.45 (d, 1H), 7.50-7.57 (m, 1H),7.79 (d, 2H), 8.18 (d., 1H), 8.58 (tr, 1H), 8.87 (d, 1H), 9.01 (s, 1H).

UPLC-MS (ESI+): [M+H]⁺=650; R_(t)=1.44 min (Method E).

The following amides in Table 12 were prepared in analogy to example2-179 starting from example 2-123 and the corresponding amines.

TABLE 12 Example Structure/Name Analytical data 2-180

 

  (±) N-(2-chlorophenyl)-2-[(2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]acetamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.16 (m, 10H), 1.33- 1.48 (m,2H), 1.65-1.94 (m, 3H), 2.02 (t, 1H), 4.55-4.69 (m, 1H), 4.75 (s, 2H),6.73-6.81 (m, 1H), 7.08 (d, 1H), 7.17-7.26 (m, 1H), 7.27-7.40 (m, 3H),7.43-7.57 (m, 2H), 7.79 (d, 2H), 7.89-7.96 (m, 1H), 9.02 (s, 1H), 9.58(s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 602; R_(t) = 1.57 min (Method E).2-181

 

  (±) N-[(3-methylpyridin-2- yl)methyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.94-1.10 (m, 10H), 1.34- 1.46 (m, 2H), 1.68-1.93 (m, 3H), 2.02 (t, 1H),2.28 (s, 3H), 4.47 (d, 2H), 4.53-4.69 (m, 3H), 6.72- 6.79 (m, 1H), 7.06(s, 1H), 7.18- 7.25 (m, 1H), 7.31 (d, 2H), 7.44 (d, 1H), 7.58 (d, 1H),7.79 (d, 2H), 8.39 (m, 1H), 8.44-8.50 (m, 1H), 8.98 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 596; R_(t) = 1.25 min (Method E). 2-182

 

  (±) N-[(3-fluoropyridin-2-yl)methyl]- 2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.92-1.15 (m, 10H), 1.32- 1.55 (m, 2H), 1.64-1.94 (m, 3H), 2.03 (t, 1H),4.48-4.70 (m, 5H), 6.76-6.86 (m, 1H), 7.00 (m, 1H), 7.32-7.45 (m, 3H),7.65-7.77 (m, 3H), 8.39 (m, 1H), 8.57 (t, 1H). UPLC-MS (ESI+): [M + H]⁺= 600; R_(t) = 1.27 min (Method E). 2-183

 

  (±) N-{[3-chloro-5- (trifluoromethyl)pyridin-2- yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.93-1.16 (m, 10H), 1.34- 1.45 (m, 2H), 1.65-1.93 (m, 3H), 2.02 (t, 1H),4.53-4.70 (m, 5H), 6.70-6.78 (m, 1H), 7.08-7.15 (m, 1H), 7.30 (d, 2H),7.45 (d, 1H), 7.81 (d, 2H), 8.45 (m, 1H), 8.63 (t, 1H), 8.98 (d, 2H).UPLC-MS (ESI+): [M + H]⁺ = 684/686; R_(t) = 1.44 min (Method E). 2-184

 

  (±) N-{[3-chloro-5- (trifluoromethyl)pyridin-2- yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide 1H-NMR (400 MHz, DMSO-d6): δ [ppm] =0.91-1.16 (m, 10H), 1.33- 1.46 (m, 2H), 1.66-1.93 (m, 3H), 2.02 (t, 1H),4.53-4.69 (m, 1H), 4.74 (s, 2H), 6.71-6.80 (m, 1H), 6.99-7.05 (m, 1H),7.30 (d, 2H), 7.46 (d, 1H), 7.59-7.82 (m, 4H), 8.88 (d, 1H), 8.99 (s,1H), 10.64 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 653; R_(t) = 1.64 min(Method E). 2-185

 

  (±) N-[3-(trifluoromethoxy)phenyl]- 2-[(2-{[4-(trifluoromethoxy)phenyl]amino)-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.90-1.15 (m, 10H), 1.34- 1.47 (m, 2H), 1.64-1.93 (m, 3H), 2.02 (t, 1H),4.53-4.68 (m, 1H), 4.70 (s, 2H), 6.71-6.80 (m, 1H), 6.99-7.10 (m, 2H),7.30 (d, 2H), 7.41-7.51 (m, 2H), 7.64(d, 1H), 7.77 (d, 2H), 7.83 (s,1H), 8.98 (s, 1H), 10.35 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 651; R_(t)= 1.57 min (Method E). 2-186

 

  (±) 2-[(2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]-N-[4-(trifluoromethyl)phenyl]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.89-1.15 (m, 10H), 1.33- 1.46 (m, 2H), 1.64-1.93 (m, 3H), 2.02 (t, 1H),4.54-4.68 (m, 1H), 4.72 (s, 2H), 6.71-6.81 (m, 1H), 6.99-7.07 (m, 1H),7.30 (d, 2H), 7.46 (d, 1H), 7.69 (d, 2H), 7.77 (d, 2H), 7.89 (d, 2H),8.98 (s, 1H), 10.43 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 635; R_(t) =1.55 min (Method E). 2-187

 

  (±) 2-[(2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]-N-[3-(trifluoromethyl)phenyl]acetamide ¹H-NMR (400 MHz, DMSO-d6): δ [ppm] =0.91-1.14 (m, 10H), 1.33- 1.46 (m, 2H), 1.66-1.93(m, 3H), 2.02 (t, 1H),4.52-4.68 (m, 1H), 4.71 (s, 2H), 6.73-6.81 (m, 1H), 7.00-7.06 (m, 1H),7.30 (d, 2H), 7.45 (t, 2H), 7.57 (t, 1H), 7.77 (d, 2H), 7.91 (d, 1H),8.15 (s, 1H), 8.98 (s, 1H), 10.40 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ =635; R_(t) = 1.53 min (Method E). 2-188

 

  (±) N-[3-(difluoromethoxy)phenyl]- 2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide 1H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.92-1.12 (m, 10H), 1.33- 1.44 (m, 2H), 1.67-1.93 (m, 3H), 2.02 (t, 1H),4.55-4.66 (m, 1H), 4.69 (s, 2H), 6.71-6.79 (m, 1H), 6.86-6.92 (m, 1H),6.99-7.04 (m, 1H), 7.19 (t, 1H), 7.30 (d, 2H), 7.34- 7.40 (m, 1H),7.42-7.53 (m, 2H), 7.62 (s, 1H), 7.78 (d, 2H), 8.99 (s, 1H), 10.24 (s,1H). UPLC-MS (ESI+): [M + H]⁺ = 633; R_(t) = 1.45 min (Method E). 2-189

 

  (±) methyl-3-({[(2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]acetyl}amino)benzoate ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.88-1.14 (m, 10H), 1.33- 1.45 (m, 2H), 1.65-1.93 (m, 3H), 2.02 (t, 1H),3.85 (s, 3H), 4.53- 4.67 (m, 1H), 4.71 (s, 2H), 6.72- 6.80 (m, 1H),7.00-7.06 (m, 1H), 7.30 (d, 2H), 7.42-7.53 (m, 2H), 7.67 (d, 1H), 7.87(d, 2H), 7.92 (d, 1H), 8.36 (s, 1H), 9.02 (s, 1H), 10.32 (s, 1H).UPLC-MS (ESI+): [M + H]⁺ = 625; R_(t) = 1.42 min (Method E). 2-190

 

  (±) N-[2-chloro-5- (difluoromethyl)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.90-1.14 (m, 10H), 1.33- 1.46 (m, 2H), 1.66-1.94 (m, 3H), 2.02 (t, 1H),4.55-4.70 (m, 1H), 4.80 (s, 2H), 6.74-6.83 (m, 1H), 7.08 (t, 1H), 7.31(d, 2H), 7.41 (d, 1H), 7.47 (d, 1H), 7.69 (d, 1H), 7.79 (d, 2H), 8.18(s, 1H), 9.02 (s, 1H), 9.70 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 652;R_(t) = 1.55 min (Method E). 2-191

 

  (±) N-[4-(difluoromethoxy)phenyl]- 2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.90-1.14 (m, 10H), 1.34- 1.45 (m, 2H), 1.67-1.92 (m, 3H), 2.02 (t, 1H),4.56-4.71 (m, 3H), 6.72-6.79 (m, 1H), 7.00-7.05 (m, 1H), 7.14 (d, 1H),7.14 (t, 1H), 7.30 (d, 2H), 7.46 (d, 1H), 7.70 (d, 2H), 7.77 (d, 2H),8.98 (s, 1H), 10.14 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 633; R_(t) =1.45 min (Method E). 2-192

 

  (±) N-(2-methylphenyl)-2-[(2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]acetamide1H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.91-1.13 (m, 10H), 1.34- 1.45 (m,2H), 1.68-1.93(m, 3H), 2.02 (t, 1H), 2.17 (s, 3H), 4.56- 4.67 (m, 1H),4.70 (s, 1H), 6.75- 6.81 (m, 1H), 7.04-7.25 (m, 4H), 7.30 (d, 2H),7.41-7.50 (m, 2H), 7.79 (d, 2H), 8.99 (s, 1H), 9.42 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 581; R_(t) = 1.36 min (Method E). 2-193

 

  (±) N-(3-methylphenyl)-2-[(2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)oxy]acetamide¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.91-1.12 (m, 10H), 1.34- 1.44 (m,2H), 1.67-1.92 (m, 3H), 2.02 (t, 1H), 2.27 (s, 3H), 4.56- 4.70 (m, 3H),6.72-6.78 (m, 1H), 6.87-6.91 (m, 1H), 7.19 (t, 1H), 7.30 (d, 2H), 7.45(d, 2H), 7.50 (s, 1H), 7.77 (d, 2H), 8.98 (s, 1H), 9.95 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 581; R_(t) = 1.45 min (Method E). 2-194

 

  (±) N-[4-(trifluoromethoxy)phenyl]- 2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide ¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] =0.91-1.13 (m, 10H), 1.34- 1.45 (m, 2H), 1.67-1.93 (m, 3H), 2.02 (t, 1H),4.56-4.72 (m, 3H), 6.72-6.79 (m, 1H), 7.00-7.06 (m, 1H), 7.26-7.37 (m,4H), 7.45 (d, 1H), 7.74-7.83 (m, 4H), 8.98 (s, 1H), 10.27 (s, 1H).UPLC-MS (ESI+): [M + H]⁺ = 651; R_(t) = 1.57 min (Method E).

The examples in Table 13 were prepared in an analogous manner toreference example 2-1, starting from the intermediates 1-34-1-44 and thecorresponding commercially available thioisocyanates. The enantiomerswere separated and analyzed according to the given procedures.

TABLE 13 Example Structure/Name Analytical data 2-195

  methyl [1-(3,3,5,5- tetramethylcyclohexyl)-2{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.10 (s, 6H), 1.22-1.36 (m,2H), 1.50-1.58 (m, 2H), 2.04 (t, 2H), 3.60 (s, 3H), 3.69 (s, 2H),4.56-4.67 (m, 1H), 6.72- 6.78 (m, 1H), 6.90-6.97 (m, 1H), 7.26-7.33 (m,3H), 7.52 (d, 1H), 7.84 (d, 2H), 8.97 (s, 1H). UPLC-MS (ESI+): [M + H]⁺= 504; R_(t) = 1.63 min (Method E).| 2-196

  methyl [2-{[4-(propan-2- yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.96 (s, 6H), 1.10 (s, 6H), 1.22-1.34 (m, 8H),1.47-1.55 (m, 2H), 2.02 (t, 2H), 3.60 (s, 3H), 3.66 (s, 2H), 4.47-4.63(m, 2H), 6.83- 6.91 (m, 4H), 7.17-7.21 (m, 1H), 7.40-7.47 (m, 3H), 8.53(s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 478; R_(t) = 1.60 min (Method D).|2-197

  methyl [2-{[4-(propan-2- yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.96 (s, 6H), 1.07 (s, 6H), 1.19 (d, 6H), 1.22-1.34(m, 2H), 1.47-1.56 (m, 2H), 2.02 (t, 2H), 2.78-2.90 (m, 1H), 3.60 (s,3H), 3.67 (s, 2H), 4.53-4.64 (m, 1H), 6.86-6.92 (m, 1H), 7.17 (d, 2H),7.21-7.25 (m, 1H), 7.40 (d, 2H), 7.46 (d, 1H), 8.65 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 462; R_(t) = 1.68 min (Method D).| 2-198

 

  (±) methyl (2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.92-1.13 (m, 10H), 1.20 (d, 6H), 1.34-1.44 (m, 2H),1.68- 1.93 (m, 3H), 2.02 (t, 1H), 2.79- 2.90 (m, 1H), 3.60 (s, 3H), 3.67(s, 2H), 4.56-4.68 (m, 1H), 6.84- 6.90 (m, 1H), 7.17 (d, 2H), 7.20- 7.24(m, 1H), 7.43 (d, 1H), 7.57 (d, 2H), 8.69 (s, 1H). UPLC-MS (ESI+): [M +H]⁺ = 448; R_(t) = 1.64 min (Method D). 2-198-1 methyl (2-{[4-(propan-2-Separation: yl)phenyl]amino}-1-[(cis)-3,3,5- System: Sepiatec: PrepSFC100; trimethylcyclohexyl]-1H- Column: Chiralpak IA 5 μmbenzimidazol-5-yl)acetate, 250 × 20 mm; enantiomer A Eluent A: CO2,Eluent B: 2- propanol; Isocratic: 30% B; Flow 80.0 mL/min; Temperature:40° C.; BPR: 150 bar; MWD: 254 nm; Analysis: System: Agilent: 1260 AS,MWD, Aurora SFC-Modul; Column: Chiralpak IA 5 μm 100 × 4,6 mm; Eluent A:CO2, Eluent B: 2- propanol; Isocratic: 30% B; Flow 4,0 ml/min;Temperature: 37.5° C.; Injection: 5 μL; BPR: 100 bar; MWD: 254 nm: R_(t)= 2.21 min. 2-198-2 methyl (2-{[4-(propan-2- R_(t) = 4.02 min.yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-199

 

  (±) methyl (2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.92-1.12 (m, 10H), 1.26 (d, 6H), 1.35-1.44 (m, 2H),1.66- 1.95 (m, 3H), 2.04 (t, 1H), 3.60 (s, 3H), 3.65 (s, 2H), 4.47-4.66(m, 2H), 6.82-6.92 (m, 3H), 7.16- 7.21 (m, 1H), 7.40 (d, 1H), 7.57 (d,2H), 8.58 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 464; R_(t) = 1.57 min(Method D). 2-199-1 methyl (2-{[4-(propan-2- Separation:yloxy)phenyl]amino}-1-[(cis)-3,3,5- System: Sepiatec: Prep SFC100,trimethylcyclohexyl]-1H- Column: Chiralpak IA 5 μm 250 × 20benzimidazol-5-yl)acetate, mm enantiomer A Solvent: CO2/2-propanol 72/28Flow: 80 mL/min Pressure(outlet): 150 bar Temperature: 40° C. Solution:260 mg/2 mL dichloromethane/methanol 1:1 Injection: 7 × 0.3 mLDetection: UV 254 nm; Analysis: System: Agilent: 1260 AS, MWD, AuroraSFC-Modul: Column: Chiralpak IA 5 μm 100 × 4.6 mm Solvent:CO2/2-propanol 72/28 Flow: 4.0 mL/min Pressure(outlet): 100 barTemperature: 37.5° C. Solution: 1.0 mg/mL EtOH/MeOH Injection: 10.0 μLDetection: DAD 254 nm: R_(t) = 2.31 min. 2-199-2 methyl(2-{[4-(propan-2- R_(t) = 3.75 min. yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate, enantiomer B 2-200

 

  (±) methyl (2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.14 (m, 10H), 1.36- 1.45 (m, 2H),1.69-1.95 (m, 3H), 2.04 (t, 1H), 3.60 (s, 3H), 3.68 (s, 2H), 4.57-4.69(m, 1H), 6.89- 6.94 (m, 1H), 7.25-7.35 (m, 3H), 7.47 (d, 1H), 7.80 (d,2H), 9.03 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 490; R_(t) = 1.60 min(Method D). 2-200-1 methyl (2-{[4- Separation:(trifluoromethoxy)phenyl]amino}-1- System: Sepiatec: Prep SFC100,[(cis)-3,3,5-trimethylcyclohexyl]-1H- Column: Chiralpak IA 5 μm 250 × 20benzimidazol-5-yl)acetate, mm enantiomer A Solvent: CO2/2-propanol 78/22Flow: 80 mL/min Pressure(outlet): 150 bar Temperature: 40° C. Solution:215 mg/2 mL dichloromethane/methanol 1:1 Injection: 7 × 0,3 mLDetection: UV 254 nm; Analysis: System: Agilent: 1260 AS, MWD, AuroraSFC-Modul: Column: Chiralpak IA 5 μm 100 × 4.6 mm Solvent:CO2/2-propanol 78/22 Flow: 4.0 mL/min Pressure(outlet): 100 barTemperature: 37.5° C. Solution: 1.0 mg/mL EtOH/MeOH Injection: 10.0 μLμLDetection: DAD 254 nm: R_(t) = 2.16 min. 2-200-2 methyl (2-{[4- R_(t) =3.91 min. (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate,enantiomer B 2-201

  methyl 3-[1-(3,3,5,5- tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]propanoate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.96 (s, 6H), 1.09 (s, 6H), 1.19-1.35 (m,3H), 1.48-1.59 (m, 2H), 2.03 (t, 2H), 2.64 (t, 2H), 2.89 (t, 2H), 3.58(s, 3H), 4.54-4.66 (m, 1H), 6.87-6.94 (m, 1H), 7.25 (s, 1H), 7.30 (d,2H), 7.48 (d, IH), 7.62 (d, 2H), 8.93 (s, 1H). UPLC-MS (ESI+): [M + H]⁺= 518; R_(t) = 1.68 min (Method F). 2-202

  methyl [6-methyl-2-{[4-(propan-2- yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.09 (s, 6H), 1.25 (d, 6H), 1.45-1.55(m, 2H), 2.03 (t, 2H), 2.29 (s, 3H), 3.60 (s, 3H), 3.67 (s, 2H),4.45-4.61 (m, 2H), 6.87 (d, 2H), 7.14 (s, 1H), 7.31 (s, 1H), 7.39 (d,2H), 8.43 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 492; R_(t) = 1.67 min(Method F). 2-203

  methyl [6-methyl-2-{[4-(propan-2- yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.96 (s, 6H), 1.04 (s, 6H), 1.19 (d, 6H), 1.21-1.36(m, 2H), 1.45-1.55 (m, 2H), 2.03 (t, 2H), 2.30 (s, 3H), 2.76-2.90 (m,1H), 3.61 (s, 3H), 3.68 (s, 2H), 4.48- 4.60 (m, 1H), 7.11-7.22 (m, 3H),7.30-7.38 (m, 3H), 8.55 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 476; R_(t) =1.75 min (Method F). 2-204

  methyl [6-methyl-1-(3,3,5,5- tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.08 (s, 6H), 1.22-1.37 (m,2H), 1.47-1.58 (m, 2H), 2.05 (t, 2H), 2.31 (s, 3H), 3.61 (s, 3H), 3.70(s, 2H), 4.51- 4.63 (m, 1H), 7.24 (s, 1H), 7.28 (d, 2H), 7.40 (s, 1H),7.56 (d, 2H), 8.88 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 518; R_(t) = 1.69min (Method F). 2-205

 

  (±) methyl (6-methyl-2-{[4-(propan- 2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.92-1.14 (m, 10H), 1.25 (d, 6H), 1.34-1.42 (m,2H), 1.69- 1.93 (m, 3H), 2.05 (t, 1H), 2.29 (s, 3H), 3.60 (s, 3H), 3.66(s, 2H), 4.45-4.63 (m, 2H), 6.87 (d, 2H), 7.13 (s, 1H), 7.27 (s, 1H),7.55 (d, 2H), 8.50 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 478; R_(t) = 1.63min (Method F). 2-205-1 methyl (6-methyl-2-{[4-(propan-2- Separation:yloxy)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep 1200,trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)acetate, FC, enantiomer A Column: Chiralpak IA 5 μm250 × 20 mm Solvent: hexane/ethanol 81:19 +0.1% DEA Flow: 15 mL/minTemperature: rt Solution: 164.5 mg/2 mL DCM/MeOH 1:1 Injection: 21 × 0,1mL Detection: UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290Column: Chiralpak IA 3 μm 100 × 4.6 mm Solvent: hexane/ethanol 79:21+0.1% DEA Flow: 1.0 mL/min Temperature: 25° C. Solution: 1.0 mg/mLEtOH/MeOH 1:1 Injection: 5.0 μL Detection: DAD 254 nm: R_(t) = 3.24 min.2-205-2 methyl (6-methyl-2-{[4-(propan-2- R_(t) = 4.14 min.yloxy)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-206

 

  (±) methyl (6-methyl-2-{[4-(propan- 2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.92-1.13 (m, 10H), 1.19 (d, 6H), 1.32-1.45 (m, 2H),1.68- 1.94 (m, 3H), 2.04 (t, 1H), 2.29 (s, 3H), 2.77-2.91 (m, 1H), 3.60(s, 3H), 3.68 (s, 2H), 4.52-4.65 (m, 1H), 7.13-7.19 (m, 3H), 7.29 (s,1H), 7.54 (d, 2H), 8.62 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 462; R_(t) =1.70 min (Method F). 2-206-1 methyl (6-methyl-2-{[4-(propan-2-Separation: yl)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep 1200,trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)acetate, FC, enantiomer A Column: Chiralpak IA 5 μm250 × 20 mm Solvent: hexane/ethanol 80:20 Flow: 15 mL/min Temperature:rt Solution: 163 mg/2 mL DCM/MeOH 1:1 Injection: 21 × 0.1 mL Detection:UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290 Column: ChiralpakIA 3 μm 100 × 4.6 mm Solvent: hexane/ethanol 78:22 Flow: 1.0 mL/minTemperature: 25° C. Solution: 1.0 mg/mL EtOH/MeOH 1:1 Injection: 5.0 μLDetection: DAD 254 nm: R_(t) = 3.26 min. 2-206-2 methyl(6-methyl-2-{[4-(propan-2- R_(t) = 4.73 min.yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-207

 

  (±) methyl (6-methyl-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.16 (m, 10H), 1.32- 1.44 (m, 2H),1.71-1.96 (m, 3H), 2.05 (t, 1H), 2.30 (s, 3H), 3.60 (s, 3H), 3.69 (s,2H), 4.55-4.67 (m, 1H), 7.21 (s, 1H), 7.29 (d, 2H), 7.35 (s, 1H), 7.76(d, 2H), 8.95 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 504; R_(t) = 1.66 min(Method F). 2-207-1 methyl (6-methyl-2-{[4- Separation:(trifluoromethoxy)phenyl]amino}-1- System: Agilent: Prep 1200,[(cis)-3,3,5-trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)acetate, FC, enantiomer A Column: Chiralpak IA 5 μm250 × 20 mm Solvent: hexane/ethanol 83:17 +0.1% DEA Flow: 15 mL/minTemperature: rt Solution: 180,6 mg/2 mL DCM/MeOH 1:1 Injection: 21 × 0,1mL Detection: UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290Column: Chiralpak IA 3 μm 100 × 4.6 mm Solvent: hexane/ethanol 81:19+0.1% DEA Flow: 1.0 mL/min Temperature: 25° C. Solution: 1.0 mg/mLEtOH/MeOH 1:1 Injection: 5.0 μL Detection: DAD 254 nm: R_(t) = 3.09 min.2-207-2 methyl (6-methyl-2-{[4- R_(t) = 4.36 min.(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-208

 

  (±) methyl 3-(1-[-3,3- dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl)propanoate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 3H), 1.04 (s, 3H), 1.33-1.44 (m,3H), 1.58-1.91 (m, 3H), 2.02-2.15 (m, 2H), 2.64 (t, 2H), 2.88 (t, 2H),3.58 (s, 3H), 4.52- 4.64 (m, 1H), 6.85-6.91 (m, 1H), 7.23 (s, 1H), 7.31(d, 2H), 7.44 (d, 1H), 7.79 (d, 2H), 8.98 (s, 1H). UPLC-MS (ESI+): [M +H]⁺ = 490; R_(t) = 1.61 min (Method F). 2-208-1 methyl 3-(1-[-3,3-Separation: dimethylcyclohexyl]-2-{[4- System: Agilent: Prep 1200,(trifluoromethoxy)phenyl]amino}- 2 × Prep Pump, DLA, MWD, Prep1H-benzimidazol-5-yl)propanoate, FC, enantiomer A Column: Chiralpak IA 5μm 250 × 20 mm Solvent: hexane/2-propanol 77:23 (v/v) Flow: 15 mL/minTemperature: rt Solution: 155,6 mg/2 mL DCM/MeOH 1:1 Injection: 6 × 0.3mL Detection: UV 254 nm; Analysis: System: Agilent 1260/Agilent 1290Column: Chiralpak IA 3 μm 100 × 4.6 mm Solvent: hexane/2-propanol 74:26(v/v) Flow: 1.0 mL/min Temperature: 25° C. Solution: 1.0 mg/mL EtOH/MeOH1:1 Injection: 5.0 μL Detection: DAD 254 nm: R_(t) = 4.88 min. 2-208-2methyl 3-(1-[-3,3- R_(t) = 8.82 min. dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl)propanoate,enantiomer B 2-209

 

  (±) methyl 3-(1-[-3,3- dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H- benzimidazol-5-yl)propanoate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.97 (s, 3H), 1.04 (s, 3H), 1.25 (d, 6H), 1.33-1.43(m, 3H), 1.60-1.88 (m, 3H), 1.98-2.13 (m, 2H), 2.63 (t, 2H), 2.86 (t,2H), 3.58 (s, 3H), 4.47-4.63 (m, 2H), 6.78-6.83 (m, 1H), 6.88 (d, 2H),7.13-7.17 (m, 1H), 7.37 (d, 1H), 7.57 (d, 2H), 8.54 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 464; R_(t) = 1.56 min (Method F). 2-209-1 methyl3-(1-[-3,3- Separation: dimethylcyclohexyl]-2-{[4-(propan- System:Agilent: Prep 1200, 2-yloxy)phenyl]amino}-1H- 2 × Prep Pump, DLA, MWD,Prep benzimidazol-5-yl)propanoate, FC enantiomer A Column: Chiralpak IA5 μm 250 × 30 mm Nr. 010 Solvent: hexane/2-propanol/ diethylamine50:50:0.1 (v/v/v) Flow: 50 mL/min Temperature: rt Solution: 2648 mg/2.5mL DCM/MeOH 1:1 Injection: 3 × 0.9 mL Detection: UV 254 nm; Analysis:System: Agilent 1260 Column: Chiralpak IA 5 μm 150 × 4.6 mm Solvent:hexane/2-propanol/ diethylamine 50:50:0.1 (v/v/v) Flow: 1.0 mL/minTemperature: 25° C. Solution: 1.0 mg/mL EtOH/MeOH 2:1 Injection: 5.0 μLDetection: DAD 254 nm: R_(t) = 3.47 min. 2-209-2 methyl 3-(1-[-3,3-R_(t) = 5.58 min. dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H- benzimidazol-5-yl)propanoate, enantiomer B2-210

 

  (±) methyl 3-(1-[-3,3- dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H- benzimidazol-5-yl)propanoate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.97 (s, 3H), 1.03 (s, 3H), 1.20 (d, 6H), 1.33-1.43(m, 3H), 1.60-1.89 (m, 3H), 2.01-2.13 (m, 2H), 2.63 (t, 2H), 2.80-2.91(m, 3H), 3.59 (s, 3H), 4.50-4.63 (m, 1H), 6.80-6.87 (m, 1H), 7.12- 7.20(m, 3H), 7.39 (d, 1H), 7.57 (d, 2H), 8.65 (s, 1H). UPLC-MS (ESI+): [M +H]⁺ = 448; R_(t) = 1.65 min (Method F). 2-210-1 methyl 3-(1-[-3,3-Separation: dimethylcyclohexyl]-2-{[4-(propan- System: Agilent: Prep1200, 2-yl)phenyl]amino}-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)propanoate, FC enantiomer A Column: Chiralpak IA 5 μm250 × 30 mm Nr. 010 Solvent: hexane/2-propanol/ diethylamine 50:50:0.1(v/v/v) Flow: 50 mL/min Temperature: rt Solution: 260 mg/4.5 mL DCM/MeOH1:1 Injection: 4 × 1.2 mL Detection: UV 254 nm; Analysis: System:Agilent 1260 Column: Chiralpak IA 5 μm 150 × 4.6 mm Solvent:hexane/2-propanol/ diethylamine 50:50:0.1 (v/v/v) Flow: 1.0 mL/minTemperature: 25° C. Solution: 1.0 mg/mL EtOH/MeOH 2:1 Injection: 5.0 μLDetection: DAD 254 nm: R_(t) = 3.78 min. 2-210-2 methyl 3-(1-[-3,3-R_(t) = 6.87 min. dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H- benzimidazol-5-yl)propanoate, enantiomer B 2-211

  methyl 3-[2-{[4-(propan-2- yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]propanoate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.96 (s, 6H), 1.10 (s, 6H), 1.25 (d, 6H), 1.46-1.54(m, 2H), 2.02 (t, 2H), 2.62 (t, 2H), 2.87 (t, 2H), 3.58 (s, 3H),4.46-4.62 (m, 2H), 6.80-6.84 (m, 1H), 6.88 (d, 2H), 7.16 (s, 1H), 7.39(d, 1H), 7.43 (d, 2H), 8.48 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 492;R_(t) = 1.66 min (Method F). 2-212

  methyl 3-[2-{[4-(propan-2- yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]propanoate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.95 (s, 6H), 1.06 (s, 6H), 1.19 (d, 6H), 1.22-1.33(m, 3H), 1.45-1.56 (m, 2H), 2.01 (t, 2H), 2.64 (t, 2H), 2.79-2.92 (m,3H), 3.59 (s, 3H), 4.51-4.63 (m, 1H), 6.81-6.89 (m, 1H), 7.13-7.25 (m,3H), 7.36-7.45 (m, 3H), 8.61 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 476;R_(t) = 1.74 min (Method F). 2-213

 

  (±) methyl (6-methoxy-2-{[4- (propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.93-1.13 (m, 10H), 1.20 (d, 6H),1.34-1.43 (m, 2H), 1.68- 1.93 (m, 3H), 2.03 (t, 1H), 2.76- 2.89 (m, 1H),3.59 (s, 3H), 3.61 (s, 2H), 3.79 (s, 3H), 4.52-4.64 (m, 1H), 6.97 (s,1H), 7.14 (d, 2H), 7.18 (s, 1H), 7.40 (d, 2H), 8.54 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 478; R_(t) = 1.66 min (Method F). 2-213-1 methyl(6-methoxy-2-{[4-(propan-2- Separation: yl)phenyl]amino}-1-[(cis)-3,3,5-Instrument: Sepiatec: Prep trimethylcyclohexyl]-1H- SFC100; Column:Chiralpak IC benzimidazol-5-yl)acetate, 5 μm 250 × 30 mm; Solvent:CO2/2- enantiomer A propanol 65/35; Buffer: 0.2% DEA; Flow: 100 mL/min;Pressure(outlet): 150 bar; Temperatur: 40° C.; DAD 254 nm; Analysis:Instrument: Agilent: 1260 AS, MWD, Aurora SFC-Modul; Column: ChiralpakIC 5 μm 100 × 4.6 mm; Solvent: CO2/2-propanol 65/35; Buffer: 0.2% DEA;Flow 4.0 mL/min; Pressure (outlet): 100 bar; Temperature: 37.5° C.;Injection: 10 μL; Solution: 1.0 mg/mL methanol; Detection: DAD 254 nm:R_(t) = 3.08 min. 2-213-2 methyl (6-methoxy-2-{[4-(propan-2- R_(t) =4.42 min. yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-214

 

  (±) methyl (6-methoxy-2-{[4- (propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.93-1.15 (m, 10H), 1.25 (d, 6H),1.36-1.45 (m, 2H), 1.67- 1.93 (m, 3H), 2.03 (t, 1H), 3.59 (s, 3H), 3.60(s, 2H), 3.79 (s, 3H), 4.45-4.67 (m, 2H), 6.86 (d, 2H), 6.96 (s, 1H),7.14 (s, 1H), 7.51 (d, 2H), 8.43 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ =494; R_(t) = 1.59 min (Method F). 2-214-1 methyl(6-methoxy-2-{[4-(propan-2- Separation:yloxy)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep 1200,trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)acetate, FC enantiomer A Column: Chiralpak ID 5 μm 250× 30 mm Solvent: hexane/ethanol/ diethylamine 70:30:0.1 (v/v/v) Flow: 35mL/min Temperature: rt Solution: 78 mg/3.6 mL MeOH Injection: 3 × 1.2 mLDetection: UV 254 nm; Analysis: System: Agilent 1290 Column: ChiralpakID 3 μm 100 × 4.6 mm Solvent: hexane +0.1% diethylamine/ethanol 70:30(v/v) Flow: 1.0 mL/min Temperature: 25° C. Solution: 1.0 mg/mL EtOH/MeOH2:1 Injection: 5.0 μL Detection: DAD 254 nm: R_(t) = 3.63 min. 2-214-2methyl (6-methoxy-2-{[4-(propan-2- R_(t) = 4.40 min.yloxy)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate enantiomer B 2-215

 

  (±) methyl (6-methoxy-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.16 (m, 10H), 1.36- 1.45 (m, 2H),1.71-1.94 (m, 3H), 2.04 (t, 1H), 3.59 (s, 3H), 3.62 (s, 2H), 3.81 (s,3H), 4.54-4.66 (m, 1H), 7.00 (s, 1H), 7.23 (s, 1H), 7.28 (d, 2H), 7.70(d, 2H), 8.88 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 520; R_(t) = 1.62 min(Method F). 2-215-1 methyl (6-methoxy-2-{[4- Separation:(trifluoromethoxy)phenynamino}-1- System: Labomatic HD3000, AS-[(cis)-3,3,5-trimethylcyclohexyl]-1H- 3000, Labcol Vario 4000 Plus,benzimidazol-5-yl)acetate, Knauer DAD 2600; enantiomer A Column:Chiralpak IA 5 μm 250 × 30 mm; Eluent A: hexane +0.1% Vol. diethylamine(99%), Eluent B: ethanol; Isocratic: 70% A + 30% B; Flow 40.0 ml/min;Temperature: rt; DAD @ 254 nm; Analysis: System: Agilent HPLC 1260;Column: Chiralpak IA 3 μm 100 × 4,6 mm; Eluent A: hexane + 0.1% Vol.diethylamine (99%), Eluent B: ethanol; Isocratic: 70% A + 30% B; Flow1.0 ml/min; Temperature: 25° C.; Injection: 5 μL; DAD at 254 nm: R_(t) =3.27 min. 2-215-2 methyl (6-methoxy-2-{[4- R_(t) = 4.32 min.(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-216

  methyl [6-fluoro-2-{[4-(propan-2- yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.96 (s, 6H), 1.05 (s, 6H), 1.19 (d, 6H), 1.33-1.41(m, 1H), 1.44-1.54 (m, 2H), 2.00 (t, 2H), 2.78-2.89 (m, 1H), 3.62 (s,3H), 3.72 (s, 2H), 4.50-4.62 (m, 1H), 7.16 (d, 2H), 7.27 (d, 1H), 7.37(d, 2H), 7.46 (d, 1H), 8.67 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 480;R_(t) = 1.69 min (Method F). 2-217

  methyl [6-fluoro-2-{[4-(propan-2- yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.09 (s, 6H), 1.25(d, 6H), 1.33-1.41(m, 1H), 1.44-1.54 (m, 2H), 2.00 (t, 2H), 3.61 (s, 3H), 3.71 (s, 2H),4.46- 4.61 (m, 2H), 6.88 (d, 2H), 7.22 (d, 1H), 7.36-7.46 (m, 3H), 8.55(s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 496; R_(t) = 1.61 min (Method D).2-218

  methyl [6-fluoro-1-(3,3,5,5- tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.08 (s, 6H), 1.17-1.43 (m,2H), 1.47-1.56 (m, 2H), 2.02 (t, 2H), 3.62 (s, 3H), 3.74 (s, 2H),4.53-4.64 (m, 1H), 7.27- 7.35 (m, 3H), 7.52 (d, 1H), 7.59 (d, 2H), 8.98(s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 522; R_(t) = 1.63 min (Method D).2-219

 

  (±) methyl (6-fluoro-2-{[4-(propan- 2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.92-1.06 (m, 9H), 1.20 (d, 6H), 1.30-1.42 (m, 2H),1.67- 1.92 (m, 3H), 2.01 (t, 1H), 2.78- 2.90 (m, 1H), 3.62 (s, 3H), 3.72(s, 2H), 4.54-4.66 (m, 1H), 7.17 (d, 2H), 7.25 (d, 1H), 7.40 (d, 1H),7.55 (d, 2H), 8.72 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 466; R_(t) = 1.64min (Method D).| 2-219-1 methyl (6-fluoro-2-{[4-(propan-2- Separation:yl)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep 1200,trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)acetate FC; enantiomer A Column: Chiralpak IC 5 μm 250× 20 mm Solvent: hexane/2-propanol 69:31 Flow: 15 mL/min Temperature: rtSolution: 66 mg/1.5 mL DCM/MeOH 1:1 Injection: 9 × 0,2 mL Detection: UV254 nm; Analysis: System: Agilent 1260/Agilent 1290 Column: Chiralpak IC3 μm 100 × 4.6 mm Solvent: hexane/2-propanol 69:31 Flow: 1.0 mL/minTemperature: 25° C. Solution: 1.0 mg/mL EtOH/MeOH 1:1 Injection: 5.0 μLLDetection: DAD 254 nm: R_(t) = 4.23 min. 2-219-2 methyl(6-fluoro-2-{[4-(propan-2- R_(t) = 5.96 min.yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-220

 

  (±) methyl (6-fluoro-2-{[4-(propan- 2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR (400MHz, DMSO-d₆): δ [ppm] = 0.92-1.06 (m, 9H), 1.10- 1.19 (m, 1H), 1.25 (d,6H), 1.31- 1.41 (m, 2H), 1.65-1.92 (m, 3H), 2.01 (t, 1H), 3.62 (s, 3H),3.70 (s, 2H), 4.46-4.64 (m, 2H), 6.88 (d, 2H), 7.21 (d, 1H), 7.37 (d,1H), 7.55 (d, 2H), 8.61 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 482; R_(t) =1.57 min (Method D). 2-220-1 methyl (6-fluoro-2-{[4-(propan-2-Separation: yloxy)phenyl]amino}-1-[(cis)-3,3,5- System: Agilent: Prep1200, trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)acetate, FC; enantiomer A Column: Chiralpak IA 5 μm250 × 30 mm Nr. 029 Solvent: hexane/ethanol/ diethylamine 80:20:0.1(v/v/v) Flow: 40 mL/min Temperature: rt Solution: 62 mg/3.6 mL DCM/MeOHInjection: 2 × 1.8 mL Detection: UV 254 nm; Analysis: System: Agilent1290 Column: Chiralpak IA 3 μm 100 × 4.6 mm Solvent: hexane/ethanol/diethylamine 80:20:0.1 (v/v/v) Flow: 1.0 mL/min Temperature: 25° C.Solution: 1.0 mg/mL EtOH/MeOH 2:1 Injection: 5.0 μLL Detection: DAD 254nm: R_(t) = 2.89 min. 2-220-2 methyl (6-fluoro-2-{[4-(propan-2- R_(t) =3.96 min. yloxy)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-221

 

  (±) methyl (6-fluoro-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.08 (m, 9H), 1.1- 1.21 (m, 1H),1.31-1.43 (m, 2H), 1.68-1.93 (m, 3H), 2.02 (t, 1H), 3.62 (s, 3H), 3.73(s, 2H), 4.56- 4.69 (m, 1H), 7.27-7.36 (m, 3H), 7.46 (d, 1H), 7.77 (d,2H), 9.05 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 508; R_(t) = 1.60 min(Method D). 2-221-1 methyl (6-fluoro-2-{[4- Separation:(trifluoromethoxy)phenyl]amino}-1- System: Agilent: Prep 1200,[(cis)-3,3,5-trimethylcyclohexyl]-1H- 2 × Prep Pump, DLA, MWD, Prepbenzimidazol-5-yl)acetate, FC; enantiomer A Column: Chiralpak IA 5 μm250 × 30 mm Solvent: hexane/ethanol/ diethylamine 80:20:0.1 (v/v/v)Flow: 40 mL/min Temperature: rt Solution: 299 mg/5.4 mL DCM/MeOHInjection: 6 × 0.9 mL Detection: UV 254 nm; Analysis: System: Agilent1290 Column: Chiralpak IA 3 μm 100 × 4.6 mm Solvent: hexane/ethanol/diethylamine 80:20:0.1 (v/v/v) Flow: 1.0 mL/min Temperature: 25° C.Solution: 1.0 mg/mL EtOH/MeOH 2:1 Injection: 5.0 μLL Detection: DAD 254nm: R_(t) = 2.62 min. 2-221-2 methyl (6-fluoro-2-{[4- R_(t) = 3.94 min.(trifluoromethoxy)phenyl]amino}-1- [(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate, enantiomer B 2-222

  methyl [6-methoxy-2-{[4-(propan-2- yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.96 (s, 6H), 1.02 (s, 6H), 1.18 (d, 6H), 1.21-1.34(m, 2H), 1.48-1.56 (m, 2H), 2.01 (t, 2H), 2.77-2.87 (m, 1H), 3.59 (s,3H), 3.62 (s, 2H), 3.79 (s, 3H), 4.50- 4.60 (m, 1H), 7.00 (s, 1H), 7.13(d, 2H), 7.21 (s, 1H), 7.26 (d, 2H), 8.47 (s, 1H). UPLC-MS (ESI+): [M +H]⁺ = 492; R_(t) = 1.66 min (Method D). 2-223

  methyl [6-methoxy-2-{[4-(propan-2- yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetate ¹H-NMR (400 MHz,DMSO-d₆): δ [ppm] = 0.98 (s, 6H), 1.06 (s, 6H), 1.24 (d, 6H), 1.47-1.56(m, 2H), 2.02 (t, 2H), 3.58 (s, 3H), 3.61 (s, 2H), 3.79 (s, 3H),4.44-4.60 (m, 2H), 6.86 (d, 2H), 6.98 (s, 1H), 7.17 (s, 1H), 7.31 (d,2H), 8.35 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 508; R_(t) = 1.57 min(Method D). 2-224

  methyl [6-methoxy-1-(3,3,5,5- tetramethylcyclohexyl)-2{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]acetate ¹H-NMR(400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.06 (s, 6H), 1.22-1.37 (m,2H), 1.49-1.58 (m, 2H), 2.04 (t, 2H), 3.59 (s, 3H), 3.63 (s, 2H), 3.80(s, 3H), 4.53-4.61 (m, 1H), 7.03 (s, 1H), 7.23-7.31 (m, 3H), 7.46 (d,2H), 8.81 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 534; R_(t) = 1.60 min(Method D).

The examples in Table 14 were prepared in an analogous manner to example2-169, starting from the given ester precursors.

TABLE 14 Ester Example Structure/Name Analytical data precursor 2-225

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.15 (m, 10H), 1.36-1.51 (m,2H), 1.70-1.95 (m, 3H), 2.06 (t, 1H), 3.59 (s, 2H), 4.61-4.73 (m, 1H),6.97 (d, 1H), 7.27 (s, 1H), 7.35 (d, 2H), 7.53 (d, 1H), 7.76 (d, 2H),12.22 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 476; R_(t) = 0.95 min (MethodB). 2-200

(±) (2-{[4- (triflouromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid2-225-1 (2-{[4- ¹H-NMR (400 MHz, 2-200-1(triflouromethoxy)phenyl]amino}-1- DMSO-d₆): δ [ppm] =[(cis)-3,3,5-trimethylcyclohexyl]-1H- 0.93-1.13 (m, 10H),benzimidazol-5-yl)acetic acid, 1.36-1.47 (m, 2H), enantiomer A 1.71-1.95(m, 3H), 2.05 (t, 1H), 3.58 (s, 2H), 4.59-4.72 (m, 1H), 6.94 (d, 1H),7.27 (s, 1H), 7.32 (d, 2H), 7.49 (d, 1H), 7.78 (d, 2H), 9.13 (sbr, 1H),12.21 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 476; R_(t) = 1.28 min (MethodE). 2-225-2 (2-{[4- ¹H-NMR (400 MHz, 2-200-2(triflouromethoxy)phenyl]amino}-1- DMSO-d₆): δ [ppm] =[(cis)-3,3,5-trimethylcyclohexyl]-1H- 0.93-1.13 (m, 10H),benzimidazol-5-yl)acetic acid, 1.36-1.47 (m, 2H), enantiomer B 1.71-1.95(m, 3H), 2.05 (t, 1H), 3.58 (s, 2H), 4.59-4.72 (m, 1H), 6.94 (d, 1H),7.27 (s, 1H), 7.32 (d, 2H), 7.49 (d, 1H), 7.78 (d, 2H), 9.13 (sbr, 1H),12.21 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 476; R_(t) = 1.28 min (MethodE). 2-226

¹H-NMR (400 MHz; DMSO-d₆): δ [ppm] = 0.92-1.10 (m, 10H), 1.29 (d, 6H),1.36- 1.42 (m, 1H), 1.51- 1.59 (m, 1H), 1.67- 1.97 (m, 3H), 2.08 (t,1H), 3.63 (s, 2H), 4.57-4.67 (m, 1H), 4.69-4.81 (m, 1H), 7.01 (d, 2H),7.06 (d, 1H), 7.23 (s, 1H), 7.46 (d, 2H), 7.64 (d, 1H), 12.30 (s, 1H).UPLC-MS (ESI+): [M + H]⁺ = 450; R_(t) = 0.90 min (Method F). 2-199

(±) (2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid 2-226-1(2-{[4-(propan-2- UPLC-MS (ESI+): 2-199-1yloxy)phenyl]amino}-1-[(cis)-3,3,5- [M + H]⁺ = 450;trimethylcyclohexyl]-1H- R_(t) = 1.25 min benzimidazol-5-yl)acetic acid,(Method E). enantiomer A 2-226-2 (2-{[4-(propan-2- UPLC-MS (ESI+):2-199-2 yloxy)phenyl]amino}-1-[(cis)-3,3,5- [M + H]⁺ = 450;trimethylcyclohexyl]-1H- R_(t) = 1.25 min benzimidazol-5-yl)acetic acid,(Method E). enantiomer B 2-227

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.99 (s, 6H), 1.13 (s, 6H),1.22-1.42 (m, 2H), 1.59-1.70 (m, 2H), 2.07 (t, 2H), 3.64 (s, 2H),4.65-4.78 (m, 1H), 7.08 (d, 1H), 7.30 (s, 1H), 7.43 (d, 2H), 7.64 (d,2H), 7.69 (d, 1H), 12.31 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 490; R_(t)= 0.96 min (Method F). 2-195 [1-(3,3,5,5-tetramethylcyclohexyl)- 2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]acetic acid 2-228

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.00 (s, 6H), 1.16 (s, 6H), 1.30(d, 6H), 1.62-1.70 (m, 2H), 2.08 (t, 2H), 3.64 (s, 2H), 4.59-4.76 (m,2H), 7.05 (d, 2H), 7.11 (d, 1H), 7.24 (s, 1H), 7.42 (d, 2H), 7.73 (d,1H), 12.30 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 464; R_(t) = 0.92 min(Method F). 2-196 [2-{[4-(propan-2- yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]acetic acid 2-229

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.09 (s, 6H), 1.20(d, 6H), 1.24 1.38 (m, 2H), 1.50-1.61 (m, 2H), 2.04 (t, 2H), 2.81- 2.94(m, 1H), 3.59 (s, 2H), 4.54-4.70 (m, 1H), 6.95 (d, 1H), 7.18-7.28 (m,2H), 7.41 (d, 2H), 7.54 (d, 1H), 12.24 (s, 1H). UPLC-MS (ESI+): [M + H]⁺= 448; R_(t) = 0.99 min (Method F). 2-197[2-{[4-(propan-2-yl)phenyl]amino}- 1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetic acid 2-230

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 3H), 1.03 (s, 3H),1.33-1.43 (m, 3H), 1.63-2.12 (m, 5H), 2.53 (t, 2H), 2.86 (t, 2H),4.51-4.64 (m, 1H), 6.88 (d, 1H), 7.23 (s, 1H), 7.30 (d, 2H), 7.43 (d,1H), 7.78 (d, 2H), 8.96 (s, 1H), 12.05 (s, 1H). UPLC-MS (ESI+): [M + H]⁺= 476; R_(t) = 1.09 min (Method E). 2-201

(±) 3-(1-[3,3-dimethylcyclohexyl]-2- {[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl)propanoic acid2-230-1 3-(1-[3,3-dimethylcyclohexyl]-2-{[4- ¹H-NMR (400 MHz, 2-201-1(trifluoromethoxy)phenyl]amino}- DMSO-d₆): δ [ppm] =1H-benzimidazol-5-yl)propanoic 0.97 (s, 3H), 1.03 (s, acid, enantiomer A3H), 1.33-1.43 (m, 3H), 1.63-2.12 (m, 5H), 2.53 (t, 2H), 2.86 (t, 2H),4.51-4.64 (m, 1H), 6.88 (d, 1H), 7.23 (s, 1H), 7.30 (d, 2H), 7.43 (d,1H), 7.78 (d, 2H), 8.96 (s, 1H), 12.05 (s, 1H). UPLC-MS (ESI+): [M + H]⁺= 476; R_(t) = 0.93 min (Method F). 2-230-23-(1-[3,3-dimethylcyclohexyl]-2-{[4- ¹H-NMR (400 MHz, 2-201-2(trifluoromethoxy)phenyl]amino}- DMSO-d₆): δ [ppm] =1H-benzimidazol-5-yl)propanoic 0.97 (s, 3H), 1.03 (s, acid, enantiomer B3H), 1.33-1.43 (m, 3H), 1.63-2.12 (m, 5H), 2.53 (t, 2H), 2.86 (t, 2H),4.51-4.64 (m, 1H), 6.88 (d, 1H), 7.23 (s, 1H), 7.30 (d, 2H), 7.43 (d,1H), 7.78 (d, 2H), 8.96 (s, 1H), 12.05 (s, 1H). UPLC-MS (ESI+): [M + H]⁺= 476; R_(t) = 0.93 min (Method F). 2-231

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.10 (m, 10H), 1.24 (d, 6H),1.34- 1.42 (m, 1H), 1.53- 1.63 (m, 1H), 1.67- 2.00 (m, 3H), 2.09 (t,1H), 2.88-3.01 (m, 1H), 3.66 (s, 2H), 4.74-4.89 (m, 1H), 7.13 (d, 1H),7.27 (s, 1H), 7.37 (d, 2H), 7.45 (d, 2H), 7.72 (d, 1H), 12.36 (s, 1H).UPLC-MS (ESI+): [M + H]⁺ = 434; R_(t) = 0.97 min (Method F). 2-198

(±) (2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid 2-231-1(2-{[4-(propan-2-yl)phenyl]amino}- ¹H-NMR (400 MHz, 2-198-11-[(cis)-3,3,5-trimethylcyclohexyl]- DMSO-d₆): δ [ppm] =1H-benzimidazol-5-yl)acetic acid, 0.92-1.10 (m, 10H), enantiomer A 1.24(d, 6H), 1.34- 1.42 (m, 1H), 1.53- 1.63 (m, 1H), 1.67- 2.00 (m, 3H),2.09 (t, 1H), 2.88-3.01 (m, 1H), 3.66 (s, 2H), 4.74-4.89 (m, 1H), 7.13(d, 1H), 7.27 (s, 1H), 7.37 (d, 2H), 7.45 (d, 2H), 7.72 (d, 1H), 12.36(s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 434; R_(t) = 1.22 min (Method E).2-231-2 (2-{[4-(propan-2-yl)phenyl]amino}- ¹H-NMR (400 MHz, 2-198-21-[(cis)-3,3,5-trimethylcyclohexyl]- DMSO-d₆): δ [ppm] =1H-benzimidazol-5-yl)acetic acid, 0.92-1.10 (m, 10H), enantiomer B 1.24(d, 6H), 1.34- 1.42 (m, 1H), 1.53- 1.63 (m, 1H), 1.67- 2.00 (m, 3H),2.09 (t, 1H), 2.88-3.01 (m, 1H), 3.66 (s, 2H), 4.74-4.89 (m, 1H), 7.13(d, 1H), 7.27 (s, 1H), 7.37 (d, 2H), 7.45 (d, 2H), 7.72 (d, 1H), 12.36(s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 434; R_(t) = 1.22 min (Method E).2-232

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.00 (s, 6H), 1.14 (s, 6H), 1.25(d, 6H), 1.36-1.45 (m, 1H), 1.62-1.72 (m, 2H), 2.08 (t, 2H), 2.55 (t,2H), 2.89 (t, 2H), 2.91- 3.02 (m, 1H), 4.67- 4.80 (m, 1H), 7.15 (d, 1H),7.22 (s, 1H), 7.36-7.45 (m, 4H), 7.76 (d, 1H), 10.53 (sbr, 1H), 12.80(s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 462; R_(t) = 1.30 min (Method E).2-212 3-[2-{[4-(propan-2- yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H- benzimidazol-5-yl]propanoic acid 2-233

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.00 (s, 3H), 1.06 (s, 3H), 1.24(d, 6H), 1.32-1.49 (m. 2H), 1.55-1.63 (m, 1H), 1.66-1.76 (m, 2H),1.91-2.19 (m, 3H), 2.54 (t, 2H), 2.89 (t, 2H), 2.91-3.01 (m, 1H),4.70-4.84 (m, 1H), 7.13 (d, 1H), 7.22 (s, 1H), 7.37 (d, 2H), 7.44 (d,2H), 7.71 (d, 1H), 12.84 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 434; R_(t)= 0.92 min (Method F). 2-210

(±) 3-(1-[3,3-dimethylcyclohexyl]-2- {[4-(propan-2-yl)phenyl]amino}-1H-benzimidazol-5-yl)propanoic acid 2-233-13-(1-[3,3-dimethylcyclohexyl]-2- ¹H-NMR (400 MHz, 2-210-1{[4-(propan-2-yl)phenyl]amino}-1H- DMSO-d₆): δ [ppm] =benzimidazol-5-yl)propanoic acid, 1.00 (s, 3H), 1.05 (s, enantiomer A3H), 1.24 (d, 6H), 1.33-1.46 (m, 2H), 1.48-1.59 (m, 1H), 1.64-1.78 (m,2H), 1.89-2.17 (m, 3H), 2.54 (t, 2H), 2.84- 2.97 (m, 3H), 4.64- 4.77 (m,1H), 7.05 (d, 1H), 7.21 (s, 1H), 7.32 (d, 2H), 7.47 (d, 2H), 7.62 (d,1H), 12.10 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 434; R_(t) = 0.88 min(Method D). 2-233-2 3-(1-[3,3-dimethylcyclohexyl]-2- ¹H-NMR (400 MHz,2-210-2 {[4-(propan-2-yl)phenyl]amino}-1H- DMSO-d₆): δ [ppm] =benzimidazol-5-yl)propanoic acid, 1.00 (s, 3H), 1.05 (s, enantiomer B3H), 1.24 (d, 6H), 1.33-1.46 (m, 2H), 1.48-1.59 (m, 1H), 1.64-1.78 (m.2H), 1.89-2.17 (m, 3H), 2.54 (t, 2H), 2.84- 2.97 (m, 3H), 4.64- 4.77 (m,1H), 7.05 (d, 1H), 7.21 (s, 1H), 7.32 (d, 2H), 7.47 (d, 2H), 7.62 (d,1H), 12.10 (s. 1H). UPLC-MS (ESI+): [M + H]⁺ = 434; R_(t) = 0.88 min(Method D). 2-234

UPLC-MS (ESI+): [M + H]⁺ = 450; R_(t) = 0.86 min (Method F). 2-209

(±) 3-(1-[3,3-dimethylcyclohexyl]-2- {[4-(propan-2-yloxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoic acid 2-234-13-(1-[3,3-dimethylcyclohexyl]-2-{[4- UPLC-MS (ESI+): 2-209-1(propan-2-yloxy)phenyl]amino}-1H- [M + H]⁺ = 450;benzimidazol-5-yl)propanoic acid, R_(t) = 1.21 min enantiomer A (MethodE). 2-234-2 3-(1-[3,3-dimethylcyclohexyl]-2-{[4- UPLC-MS (ESI+): 2-209-2(propan-2-yloxy)phenyl]amino}-1H- [M + H]⁺ = 450;benzimidazol-5-yl)propanoic acid, R_(t) = 1.21 min enantiomer B (MethodE). 2-235

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.09 (s, 6H),1.19-1.36 (m, 3H), 1.49-1.58 (m, 2H), 2.03 (t, 2H), 2.54 (t, 2H), 2.86(t, 2H), 4.54-4.67 (m, 1H), 6.91 (d, 1H), 7.25 (s, 1H), 7.30 (d, 2H),7.47 (d, 1H), 7.61 (d, 2H), 8.93 (sbr, 1H). 12.06 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 504; R_(t) = 1.20 min (Method A). 2-2013-[1-(3,3,5,5- tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]propanoic acid2-236

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.93-1.05 (m, 9H), 1.36-1.45 (m,2H), 1.71-1.93 (m, 3H), 2.06 (t, 1H), 2.32 (s, 3H), 3.59 (s, 2H),4.55-4.68 (m, 1H), 7.21 (s, 1H), 7.32 (d, 2H), 7.36 (s, 1H), 7.74 (d,2H), 12.21 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 490; R_(t) = 1.18 min(Method E). 2-207

(±) (6-methyl-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid2-236-1 (6-methyl-2-{[4- ¹H-NMR (400 MHz, 2-207-1(trifluoromethoxy)phenyl]amino}-1- DMSO-d₆): δ [ppm] =[(cis)-3,3,5-trimethylcyclohexyl]-1H- 0.93-1.08 (m, 9H),benzimidazol-5-yl)acetic acid, 1.35-1.62 (m, 2H), enantiomer A 1.72-1.97(m, 3H), 2.11 (t, 1H), 2.35 (s, 3H), 3.67 (s, 2H), 4.68-4.82 (m, 1H),7.24 (s, 1H), 7.48 (d, 2H), 7.60 (s, 1H), 7.65 (d, 2H), 12.36 (sbr, 1H).UPLC-MS (ESI+): [M + H]⁺ = 490; R_(t) = 0.94 min (Method F). 2-236-2(6-methyl-2-{[4- ¹H-NMR (400 MHz, 2-207-2(trifluoromethoxy)phenyl]amino}-1- DMSO-d₆): δ [ppm] =[(cis)-3,3,5-trimethylcyclohexyl]-1H- 0.93-1.08 (m, 9H),benzimidazol-5-yl)acetic acid, 1.35-1.62 (m, 2H), enantiomer B 1.72-1.97(m, 3H), 2.11 (t, 1H), 2.35 (s, 3H), 3.67 (s, 2H), 4.68-4.82 (m, 1H),7.24 (s, 1H), 7.48 (d, 2H), 7.60 (s, 1H), 7.65 (d, 2H), 12.36 (sbr, 1H).UPLC-MS (ESI+): [M + H]⁺ = 490; R_(t) = 0.94 min (Method F). 2-237

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.06 (m, 9H), 1.20 (d, 6H),1.32- 1.44 (m, 2H), 1.70- 1.93 (m, 3H), 2.06 (t, 1H), 2.32 (s, 3H),2.80-2.91 (m, 1H), 3.58 (s, 2H), 4.54- 4.66 (m, 1H), 7.13- 7.23 (m, 3H),7.33 (s, 1H), 7.52 (d, 2H), 12.20 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ =448; R_(t) = 1.18 min (Method E). 2-206

(±) (6-methyl-2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid 2-237-1(6-methyl-2-{[4-(propan-2- ¹H-NMR (400 MHz, 2-206-1yl)phenyl]amino}-1-[(cis)-3,3,5- DMSO-d₆): δ [ppm] =trimethylcyclohexyl]-1H- 0.92-1.08 (m, 10H), benzimidazol-5-yl)aceticacid, 1.23 (d, 6H), 1.34- enantiomer A 1.57 (m, 2H), 1.71- 1.95 (m, 3H),2.09 (t, 1H), 2.34 (s, 3H), 2.84-2.97 (m, 1H), 3.63 (s, 2H), 4.58- 4.73(m, 1H), 7.16- 7.56 (m, 6H), 12.29 (sbr, 1H). UPLC-MS (ESI+): [M + H]⁺ =448; R_(t) = 0.91 min (Method B). 2-237-2 (6-methyl-2-{[4-(propan-2-¹H-NMR (400 MHz, 2-206-2 yl)phenyl]amino}-1-[(cis)-3,3,5- DMSO-d₆): δ[ppm] = trimethylcyclohexyl]-1H- 0.92-1.08 (m, 10H),benzimidazol-5-yl)acetic acid, 1.23 (d, 6H), 1.34- enantiomer B 1.57 (m,2H), 1.71- 1.95 (m, 3H), 2.09 (t, 1H), 2.34 (s, 3H), 2.84-2.97 (m, 1H),3.63 (s, 2H), 4.58- 4.73 (m, 1H), 7.16- 7.56 (m, 6H), 12.29 (sbr, 1H).UPLC-MS (ESI+): [M + H]⁺ = 448; R_(t) = 0.91 min (Method B). 2-238

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.07 (m, 9H), 1.26 (d, 6H),1.34- 1.47 (m, 2H), 1.68- 1.92 (m, 3H), 2.07 (t, 1H), 2.31 (s, 3H), 3.58(s, 2H), 4.44- 4.67 (m, 2H), 6.83- 7.57 (m, 6H), 12.21 (s, 1H). UPLC-MS(ESI+): [M + H]⁺ = 464; R_(t) = 1.31 min (Method E). 2-205

(±) (6-methyl-2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid 2-238-1(6-methyl-2-{[4-(propan-2- UPLC-MS (ESI+): 2-205-1yloxy)phenyl]amino}-1-[(cis)-3,3,5- [M + H]⁺ = 448;trimethylcyclohexyl]-1H- R_(t) = 0.86 min benzimidazol-5-yl)acetic acid,(Method B). enantiomer A 2-238-2 (6-methyl-2-{[4-(propan-2- UPLC-MS(ESI+): 2-205-2 yloxy)phenyl]amino}-1-[(cis)-3,3,5- [M + H]⁺ = 448;trimethylcyclohexyl]-1H- R_(t) = 0.86 min benzimidazol-5-yl)acetic acid,(Method B). enantiomer B 2-239

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.08 (s, 6H),1.21-1.38 (m, 2H), 1.46-1.54 (m, 2H), 2.05 (t, 2H), 2.32 (s, 3H), 3.59(s, 2H), 4.51-4.63 (m, 1H), 7.23 (s, 1H), 7.28 (d, 2H), 7.38 (s, 1H),7.55 (d, 2H), 8.87 (s, 1H), 12.22 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ =504; R_(t) = 1.22 min (Method C). 2-204 [6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4- (trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]acetic acid 2-240

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.99 (s, 6H), 1.10 (s, 6H), 1.22(d, 6H), 1.35-1.42 (m, 1H), 1.54-1.63 (m, 2H), 2.07 (t, 2H), 2.34 (s,3H), 2.85-2.96 (m, 1H), 3.63 (s, 2H), 4.56-4.69 (m, 1H), 7.19 (s, 1H),7.29 (d, 2H), 7.37 (d, 2H), 7.51 (s, 1H), 12.30 (s, 1H). UPLC-MS (ESI+):[M + H]⁺ = 462; R_(t) = 1.22 min (Method E). 2-203[6-methyl-2-{[4-(propan-2- yl)phenyl]amino}-1-(3,3,5,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl]acetic acid 2-241

UPLC-MS (ESI+): [M + H]⁺ = 478; R_(t) = 1.43 min (Method E). 2-202[6-methyl-2-{[4-(propan-2- yloxy)phenyl]amino}-1-(3,3,5,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl]acetic acid 2-242

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.06 (s, 6H), 1.20(d, 6H), 1.33-1.43 (m, 1H), 1.47-1.58 (m, 2H), 2.01 (t, 2H), 2.80- 2.91(m, 1H), 3.63 (s, 2H), 4.52-4.63 (m, 1H), 7.20 (d, 2H), 7.26 (d, 1H),7.37 (d, 2H), 7.50 (d, 1H), 12.33 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ =466; R_(t) = 0.99 min (Method F). 2-216 [6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5- tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetic acid 2-243

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.97 (s, 6H), 1.08 (s, 6H),1.19-1.26 (m, 1H), 1.35-1.43 (m, 1H), 1.47-1.57 (m, 2H), 2.03 (t, 2H),3.64 (s, 2H), 4.54-4.66 (m, 1H), 7.28-7.35 (m, 3H), 7.49-7.63 (m, 3H),12.34 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 508; R_(t) = 0.97 min (MethodF). 2-218 [6-fluoro-1-(3,3,5,5- tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}- 1H-benzimidazol-5-yl]acetic acid 2-244

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.99 (s, 6H), 1.08 (s, 6H), 1.21(d, 6H), 1.31-1.40 (m, 1H), 1.56-1.66 (m, 2H), 2.05 (t, 2H), 2.84- 2.95(m, 1H), 3.56 (s, 2H), 3.84 (s, 3H), 4.56-4.69 (m, 1H), 6.91-7.45 (m,6H), 12.11 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 478: R_(t) = 1.33 min(Method E). 2-222 [6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5- tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetic acid 2-245

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 1.00 (s, 6H), 1.10 (s, 6H),1.22-1.40 (m, 2H), 1.57-1.69 (m, 2H), 2.07 (t, 2H), 3.58 (s, 1.5H*),3.64 (s, 0.5H*), 3.76 (s, 0.6H*), 3.85 (s, 2.4H*), 4.58-4.71 (m, 1H),6.94-7.64 (m, 6H), 12.13 (s, 1H). UPLC-MS (ESI+): [M + H]⁺ = 520; R_(t)= 1.28 min (Method E). 2-224 [6-methoxy-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4- (trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]acetic acid 2-246-1

UPLC-MS (ESI+): [M + H]⁺ = 506; R_(t) = 0.93 min (Method F). 2-215-1(6-methoxy-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid,enantiomer A 2-246-2

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.95-1.07 (m, 9H), 1.08-1.17 (m,1H), 1.35-1.43 (m, 1H), 1.48-1.57 (m, 1H), 1.71-1.97 (m, 3H), 2.07 (t,1H), 3.56 (s, 2H), 3.84 (s, 3H), 4.62-4.74 (m, 1H), 7.05-7.68 (m, 6H),12.13 (br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 506; R_(t) = 0.93 min(Method F). 2-215-2 (6-methoxy-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid,enantiomer B 2-247-1

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.97-1.09 (m, 10H), 1.25 (d, 6H),1.35- 1.44 (m, 1H), 1.54- 1.65 (m, 1H), 1.71- 1.99 (m, 3H), 2.10 (t,1H), 2.88-3.01 (m, 1H), 3.59 (s, 2H), 3.87 (s, 3H), 4.68- 4.81 (m, 1H),7.10- 7.47 (m, 6H), 12.20 (sbr, 1H). UPLC-MS (ESI+): [M + H]⁺ = 464;R_(t) = 0.90 min (Method D). 2-213-1 (6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetic acid, enantiomer A 2-247-2

UPLC-MS (ESI+): [M + H]⁺ = 464; R_(t) = 0.90 min (Method D). 2-213-2(6-methoxy-2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid, enantiomer B2-248-1

UPLC-MS (ESI+): [M + H]⁺ = 480; R_(t) = 0.93 min (Method F). 2-214-1(6-methoxy-2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid, enantiomer A2-248-2

UPLC-MS (ESI+): [M + H]⁺ = 480; R_(t) = 0.93 min (Method F). 2-214-2(6-methoxy-2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid, enantiomer B2-249-1

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.94-1.07 (m, 9H), 1.23 (d, 6H),1.30- 1.39 (m, 1H), 1.45- 1.54 (m, 1H), 1.67- 1.95 (m, 3H), 2.06 (t,1H), 2.84-2.96 (m, 2H), 3.68 (s, 2H), 4.62-4.77 (m, 1H), 7.24-7.74 (m,6H), 12.45 (br. s., 1H). UPLC-MS (ESI+): [M + H]⁺ = 452; R_(t) = 0.97min (Method F). 2-219-1 (6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5- trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetic acid, enantiomer A 2-249-2

UPLC-MS (ESI+): [M + H]⁺ = 452; R_(t) = 0.97 min (Method F). 2-219-2(6-fluoro-2-{[4-(propan-2- yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid, enantiomer B2-250-1

UPLC-MS (ESI+): [M + H]⁺ = 468; R_(t) = 0.92 min (Method F). 2-220-1(6-fluoro-2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid, enantiomer A2-250-2

UPLC-MS (ESI+): [M + H]⁺ = 468; R_(t) = 0.92 min (Method F). 2-220-2(6-fluoro-2-{[4-(propan-2- yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazok-5-yl)acetic acid, enantiomer B2-251-1

¹H-NMR (400 MHz, DMSO-d₆): δ [ppm] = 0.92-1.08 (m, 9H), 1.13-1.26 (m,1H), 1.28-1.39 (m, 1H), 1.41-1.52 (m, 1H), 1.66-1.95 (m, 3H), 2.06 (t,1H), 3.66 (s, 2H), 4.61-4.76 (m, 1H), 7.24-7.82 (m, 6H), 12.42 (br. s.,1H). UPLC-MS (ESI+): [M + H]⁺ = 494; R_(t) = 0.95 min (Method F).2-221-1 (6-fluoro-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid,enantiomer A 2-251-2

UPLC-MS (ESI+): [M + H]⁺ = 494; R_(t) = 0.95 min (Method F). 2-221-2(6-fluoro-2-{[4- (trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H- benzimidazol-5-yl)acetic acid,enantiomer B

Example 2-252 methyl3-[4-fluoro-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]propanoate

In analogy to reference example 2-150: A solution of methyl3-{3-amino-2-fluoro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}propanoate(intermediate 1-45; 451 mg, 1.28 mmol) in THF (10 mL) was treated with1-isothiocyanato-4-(trifluoromethoxy)benzene (CAS No. [64285-95-6]; 1.00eq., 282 mg, 1.28 mmol) and stirred at rt for 1 h. EDC (1.16 eq., 283mg, 1.48 mmol) was added, the reaction mixture heated to 75° C. andstirring at this temperature continued for 18 hours. Further EDC (1.16eq., 283 mg, 1.48 mmol) was added and the reaction was heated for afurther 1 h. Water (20 mL) was added, the layers were separated and theaqueous layer extracted with ethyl acetate (3×20 mL). The combinedorganic layers were dried over solid sodium sulfate and concentratedunder vacuum. The crude material was purified twice by flashchromatography (SiO₂-heptane/ethyl acetate) to give the title compound(325 mg, 47%) as a pink solid.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.88 (s, 6H), 0.95 (s, 6H), 0.88-1.30(m, 4H), 1.90 (t, 2H), 2.68 (t, 2H), 3.06 (t, 2H), 3.68 (s, 3H), 4.37(t, 1H), 6.75 (br s, 1H), 6.95 (d, 1H), 7.09-7.25 (m, 5H).

LC-MS (ES+): [M+H]⁺=536; R_(t)=2.66 min (Method A).

Example 2-253 methyl3-{4-fluoro-2-[(4-isopropoxyphenyl)amino]-1-(3,3,5,5-tetramethylcyclo-hexyl)-1H-benzimidazol-5-yl}propanoate

In analogy to reference example 2-150: A solution of methyl3-{3-amino-2-fluoro-4-[(3,3,5,5-tetramethylcyclohexyl)amino]phenyl}propanoate(intermediate 1-45; 245 mg, 0.70 mmol) in THF (10 mL) was treated with1-isothiocyanato-4-(propan-2-yloxy)benzene (CAS No. [50785-46-1]; 1.00eq., 135 mg, 0.70 mmol) and stirred at rt for 1 h. EDC (1.14 eq., 154mg, 0.80 mmol) was added, the reaction mixture heated to 75° C. andstirring at this temperature continued for 18 hours. Water (20 mL) wasadded, the layers were separated and the aqueous layer extracted withethyl acetate (3×20 mL). The combined organic layers were dried oversolid sodium sulfate and concentrated under vacuum. The crude materialwas purified by flash chromatography (SiO₂-heptane/ethyl acetate) togive the title compound (77 mg, 21%) as a brown solid.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.83 (s, 6H), 0.93 (s, 6H), 1.23-1.56(m, 4H), 1.33 (d, 6H), 1.89 (t, 2H), 2.66 (t, 2H), 3.05 (t, 2H), 3.68(s, 3H), 4.20-5.55 (m, 2H), 6.07 (s, 1H), 6.80-6.90 (m 4H), 7.00-7.25(m, 2H).

LC-MS (ES+): [M+H]⁺=510; R_(t)=2.02 min (Method A).

Example 2-2543-[4-fluoro-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]propanoicacid

To a solution of methyl3-[4-fluoro-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]propanoate(example 2-252; 224 mg, 0.418 mmol) in THF (33 mL) and water (8 mL) wasadded lithium hydroxide monohydrate (4.00 eq., 70.2 mg, 1.67 mmol) andthe reaction was stirred at rt overnight. Saturated aqueous ammoniumchloride solution was added (to pH 5) and the mixture extracted withethyl acetate (3×30 mL). The combined organic layers were dried oversolid sodium sulfate and concentrated under vacuum. Purification of thecrude material by flash chromatography (SiO₂-heptane/ethyl acetate thenmethanol/ethyl acetate) gave the title compound (173 mg, 79%) as a whitesolid.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.67 (s, 6H), 0.90 (s, 6H), 1.11-1.30(m, 2H), 1.52 (d, 2H), 1.84 (t, 2H), 2.72 (t, 2H), 3.14 (t, 2H), 4.27(t, 1H), 6.90-7.02 (m, 3H), 7.05-7.20 (m, 3H).

UPLC-MS (ESI+): [M+H]⁺=522; R_(t)=2.29 min (Method G).

Example 2-2553-{4-fluoro-2-[(4-isopropoxyphenyl)amino]-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl}propanoicacid

To a solution of methyl3-{4-fluoro-2-[(4-isopropoxyphenyl)amino]-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl}propanoate(example 2-253; 77 mg, 0.15 mmol) in THF (8 mL) and water (2 mL) wasadded lithium hydroxide monohydrate (4.0 eq., 25 mg, 0.60 mmol) and thereaction was stirred at rt overnight. Saturated aqueous ammoniumchloride solution was added (to pH 5) and the mixture extracted withethyl acetate (3×20 mL). The combined organic layers were dried oversolid sodium sulfate and concentrated under vacuum. Purification of thecrude material by flash chromatography (SiO₂-heptane/ethyl acetate then10% methanol/ethyl acetate) gave the title compound (30 mg, 40%) as apale yellow solid.

¹H-NMR (300 MHz, CDCl₃): δ [ppm]=0.66 (s, 6H), 0.88 (s, 6H), 1.00-1.25(m, 2H), 1.27 (d, 6H), 1.50 (d, 2H), 1.80 (t, 2H), 2.72 (t, 2H), 3.13(t, 2H), 4.30 (t, 1H), 4.42-4.46 (m, 1H), 6.82 (d, 2H), 6.90-6.97 (m,1H), 7.00 (d, 2H), 7.05 (d, 1H).

UPLC-MS (ESI+): [M+H]⁺=496; R_(t)=2.29 min (Method H).

Further, the compounds of formula (I) of the present invention can beconverted to any salt as described herein, by any method which is knownto the person skilled in the art. Similarly, any salt of a compound offormula (I) of the present invention can be converted into the freecompound, by any method which is known to the person skilled in the art.

Pharmaceutical Compositions of the Compounds of the Invention

This invention also relates to pharmaceutical compositions containingone or more compounds of the present invention. These compositions canbe utilised to achieve the desired pharmacological effect byadministration to a patient in need thereof. A patient, for the purposeof this invention, is a mammal, including a human, in need of treatmentfor the particular condition or disease. Therefore, the presentinvention includes pharmaceutical compositions that are comprised of apharmaceutically acceptable carrier and a pharmaceutically effectiveamount of a compound, or salt thereof, of the present invention. Apharmaceutically acceptable carrier is preferably a carrier that isrelatively non-toxic and innocuous to a patient at concentrationsconsistent with effective activity of the active ingredient so that anyside effects ascribable to the carrier do not vitiate the beneficialeffects of the active ingredient. A pharmaceutically effective amount ofcompound is preferably that amount which produces a result or exerts aninfluence on the particular condition being treated. The compounds ofthe present invention can be administered withpharmaceutically-acceptable carriers well known in the art using anyeffective conventional dosage unit forms, including immediate, slow andtimed release preparations, orally, parenterally, topically, nasally,ophthalmically, optically, sublingually, rectally, vaginally, and thelike. For oral administration, the compounds can be formulated intosolid or liquid preparations such as capsules, pills, tablets, troches,lozenges, melts, powders, solutions, suspensions, or emulsions, and maybe prepared according to methods known to the art for the manufacture ofpharmaceutical compositions. The solid unit dosage forms can be acapsule that can be of the ordinary hard- or soft-shelled gelatine typecontaining, for example, surfactants, lubricants, and inert fillers suchas lactose, sucrose, calcium phosphate, and corn starch.

In another embodiment, the compounds of this invention may be tabletedwith conventional tablet bases such as lactose, sucrose and cornstarchin combination with binders such as acacia, corn starch or gelatine,disintegrating agents intended to assist the break-up and dissolution ofthe tablet following administration such as potato starch, alginic acid,corn starch, and guar gum, gum tragacanth, acacia, lubricants intendedto improve the flow of tablet granulation and to prevent the adhesion oftablet material to the surfaces of the tablet dies and punches, forexample talc, stearic acid, or magnesium, calcium or zinc stearate,dyes, colouring agents, and flavouring agents such as peppermint, oil ofwintergreen, or cherry flavouring, intended to enhance the aestheticqualities of the tablets and make them more acceptable to the patient.Suitable excipients for use in oral liquid dosage forms includedicalcium phosphate and diluents such as water and alcohols, forexample, ethanol, benzyl alcohol, and polyethylene alcohols, either withor without the addition of a pharmaceutically acceptable surfactant,suspending agent or emulsifying agent. Various other materials may bepresent as coatings or to otherwise modify the physical form of thedosage unit. For instance tablets, pills or capsules may be coated withshellac, sugar or both. Dispersible powders and granules are suitablefor the preparation of an aqueous suspension. They provide the activeingredient in admixture with a dispersing or wetting agent, a suspendingagent and one or more preservatives. Suitable dispersing or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example those sweetening, flavouringand colouring agents described above, may also be present.

The pharmaceutical compositions of this invention may also be in theform of oil-in-water emulsions. The oily phase may be a vegetable oilsuch as liquid paraffin or a mixture of vegetable oils. Suitableemulsifying agents may be (1) naturally occurring gums such as gumacacia and gum tragacanth, (2) naturally occurring phosphatides such assoy bean and lecithin, (3) esters or partial esters derived form fattyacids and hexitol anhydrides, for example, sorbitan monooleate, (4)condensation products of said partial esters with ethylene oxide, forexample, polyoxyethylene sorbitan monooleate. The emulsions may alsocontain sweetening and flavouring agents.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil such as, for example, arachis oil, olive oil, sesameoil or coconut oil, or in a mineral oil such as liquid paraffin. Theoily suspensions may contain a thickening agent such as, for example,beeswax, hard paraffin, or cetyl alcohol. The suspensions may alsocontain one or more preservatives, for example, ethyl or n-propylp-hydroxybenzoate; one or more colouring agents; one or more flavouringagents; and one or more sweetening agents such as sucrose or saccharin.

Syrups and elixirs may be formulated with sweetening agents such as, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, and preservative, such asmethyl and propyl parabens and flavouring and colouring agents.

The compounds of this invention may also be administered parenterally,that is, subcutaneously, intravenously, intraocularly, intrasynovially,intramuscularly, or interperitoneally, as injectable dosages of thecompound in preferably a physiologically acceptable diluent with apharmaceutical carrier which can be a sterile liquid or mixture ofliquids such as water, saline, aqueous dextrose and related sugarsolutions, an alcohol such as ethanol, isopropanol, or hexadecylalcohol, glycols such as propylene glycol or polyethylene glycol,glycerol ketals such as 2,2-dimethyl-1,1-dioxolane-4-methanol, etherssuch as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acidester or, a fatty acid glyceride, or an acetylated fatty acid glyceride,with or without the addition of a pharmaceutically acceptable surfactantsuch as a soap or a detergent, suspending agent such as pectin,carbomers, methylcellulose, hydroxypropylmethylcellulose, orcarboxymethylcellulose, or emulsifying agent and other pharmaceuticaladjuvants.

Illustrative of oils which can be used in the parenteral formulations ofthis invention are those of petroleum, animal, vegetable, or syntheticorigin, for example, peanut oil, soybean oil, sesame oil, cottonseedoil, corn oil, olive oil, petrolatum and mineral oil. Suitable fattyacids include oleic acid, stearic acid, isostearic acid and myristicacid. Suitable fatty acid esters are, for example, ethyl oleate andisopropyl myristate. Suitable soaps include fatty acid alkali metal,ammonium, and triethanolamine salts and suitable detergents includecationic detergents, for example dimethyl dialkyl ammonium halides,alkyl pyridinium halides, and alkylamine acetates; anionic detergents,for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether,and monoglyceride sulfates, and sulfosuccinates; non-ionic detergents,for example, fatty amine oxides, fatty acid alkanolamides, andpoly(oxyethylene-oxypropylene)s or ethylene oxide or propylene oxidecopolymers; and amphoteric detergents, for example,alkyl-beta-aminopropionates, and 2-alkylimidazoline quaternary ammoniumsalts, as well as mixtures.

The parenteral compositions of this invention will typically containfrom about 0.5% to about 25% by weight of the active ingredient insolution. Preservatives and buffers may also be used advantageously. Inorder to minimise or eliminate irritation at the site of injection, suchcompositions may contain a non-ionic surfactant having ahydrophile-lipophile balance (HLB) preferably of from about 12 to about17. The quantity of surfactant in such formulation preferably rangesfrom about 5% to about 15% by weight. The surfactant can be a singlecomponent having the above HLB or can be a mixture of two or morecomponents having the desired HLB.

Illustrative of surfactants used in parenteral formulations are theclass of polyethylene sorbitan fatty acid esters, for example, sorbitanmonooleate and the high molecular weight adducts of ethylene oxide witha hydrophobic base, formed by the condensation of propylene oxide withpropylene glycol.

The pharmaceutical compositions may be in the form of sterile injectableaqueous suspensions. Such suspensions may be formulated according toknown methods using suitable dispersing or wetting agents and suspendingagents such as, for example, sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethyl-cellulose, sodium alginate,polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing orwetting agents which may be a naturally occurring phosphatide such aslecithin, a condensation product of an alkylene oxide with a fatty acid,for example, polyoxyethylene stearate, a condensation product ofethylene oxide with a long chain aliphatic alcohol, for example,heptadeca-ethyleneoxycetanol, a condensation product of ethylene oxidewith a partial ester derived form a fatty acid and a hexitol such aspolyoxyethylene sorbitol monooleate, or a condensation product of anethylene oxide with a partial ester derived from a fatty acid and ahexitol anhydride, for example polyoxyethylene sorbitan monooleate.

The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent. Diluents and solvents that may be employed are, for example,water, Ringer's solution, isotonic sodium chloride solutions andisotonic glucose solutions. In addition, sterile fixed oils areconventionally employed as solvents or suspending media. For thispurpose, any bland, fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid can be usedin the preparation of injectables.

A composition of the invention may also be administered in the form ofsuppositories for rectal administration of the drug. These compositionscan be prepared by mixing the drug with a suitable non-irritationexcipient which is solid at ordinary temperatures but liquid at therectal temperature and will therefore melt in the rectum to release thedrug. Such materials are, for example, cocoa butter and polyethyleneglycol.

Another formulation employed in the methods of the present inventionemploys transdermal delivery devices (“patches”). Such transdermalpatches may be used to provide continuous or discontinuous infusion ofthe compounds of the present invention in controlled amounts. Theconstruction and use of transdermal patches for the delivery ofpharmaceutical agents is well known in the art (see, e.g., U.S. Pat. No.5,023,252, issued Jun. 11, 1991, incorporated herein by reference). Suchpatches may be constructed for continuous, pulsatile, or on demanddelivery of pharmaceutical agents.

Controlled release formulations for parenteral administration includeliposomal, polymeric microsphere and polymeric gel formulations that areknown in the art.

It may be desirable or necessary to introduce the pharmaceuticalcomposition to the patient via a mechanical delivery device. Theconstruction and use of mechanical delivery devices for the delivery ofpharmaceutical agents is well known in the art. Direct techniques for,for example, administering a drug directly to the brain usually involveplacement of a drug delivery catheter into the patient's ventricularsystem to bypass the blood-brain barrier. One such implantable deliverysystem, used for the transport of agents to specific anatomical regionsof the body, is described in U.S. Pat. No. 5,011,472, issued Apr. 30,1991.

The compositions of the invention can also contain other conventionalpharmaceutically acceptable compounding ingredients, generally referredto as carriers or diluents, as necessary or desired. Conventionalprocedures for preparing such compositions in appropriate dosage formscan be utilized. Such ingredients and procedures include those describedin the following references, each of which is incorporated herein byreference: Powell, M. F. et al., “Compendium of Excipients forParenteral Formulations” PDA Journal of Pharmaceutical Science &Technology 1998, 52(5), 238-311; Strickley, R. G “ParenteralFormulations of Small Molecule Therapeutics Marketed in the UnitedStates (1999)-Part-1” PDA Journal of Pharmaceutical Science & Technology1999, 53(6), 324-349; and Nema, S. et al., “Excipients and Their Use inInjectable Products” PDA Journal of Pharmaceutical Science & Technology1997, 51(4), 166-171.

Commonly used pharmaceutical ingredients that can be used as appropriateto formulate the composition for its intended route of administrationinclude:

acidifying agents (examples include but are not limited to acetic acid,citric acid, fumaric acid, hydrochloric acid, nitric acid);

alkalinizing agents (examples include but are not limited to ammoniasolution, ammonium carbonate, diethanolamine, monoethanolamine,potassium hydroxide, sodium borate, sodium carbonate, sodium hydroxide,triethanolamine, trolamine);

adsorbents (examples include but are not limited to powdered celluloseand activated charcoal);

aerosol propellants (examples include but are not limited to carbondioxide, CCl₂F₂, F₂ClC—CClF₂ and CClF₃)

air displacement agents (examples include but are not limited tonitrogen and argon);

antifungal preservatives (examples include but are not limited tobenzoic acid, butylparaben, ethylparaben, methylparaben, propylparaben,sodium benzoate);

antimicrobial preservatives (examples include but are not limited tobenzalkonium chloride, benzethonium chloride, benzyl alcohol,cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol,phenylmercuric nitrate and thimerosal);

antioxidants (examples include but are not limited to ascorbic acid,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,hypophosphorus acid, monothioglycerol, propyl gallate, sodium ascorbate,sodium bisulfite, sodium formaldehyde sulfoxylate, sodiummetabisulfite);

binding materials (examples include but are not limited to blockpolymers, natural and synthetic rubber, polyacrylates, polyurethanes,silicones, polysiloxanes and styrene-butadiene copolymers);

buffering agents (examples include but are not limited to potassiummetaphosphate, dipotassium phosphate, sodium acetate, sodium citrateanhydrous and sodium citrate dihydrate)

carrying agents (examples include but are not limited to acacia syrup,aromatic syrup, aromatic elixir, cherry syrup, cocoa syrup, orangesyrup, syrup, corn oil, mineral oil, peanut oil, sesame oil,bacteriostatic sodium chloride injection and bacteriostatic water forinjection)

chelating agents (examples include but are not limited to edetatedisodium and edetic acid)

colourants (examples include but are not limited to FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel and ferric oxide red);

clarifying agents (examples include but are not limited to bentonite);

emulsifying agents (examples include but are not limited to acacia,cetomacrogol, cetyl alcohol, glyceryl monostearate, lecithin, sorbitanmonooleate, polyoxyethylene 50 monostearate);

encapsulating agents (examples include but are not limited to gelatinand cellulose acetate phthalate)

flavourants (examples include but are not limited to anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin);

humectants (examples include but are not limited to glycerol, propyleneglycol and sorbitol);

levigating agents (examples include but are not limited to mineral oiland glycerin);

oils (examples include but are not limited to arachis oil, mineral oil,olive oil, peanut oil, sesame oil and vegetable oil);

ointment bases (examples include but are not limited to lanolin,hydrophilic ointment, polyethylene glycol ointment, petrolatum,hydrophilic petrolatum, white ointment, yellow ointment, and rose waterointment);

penetration enhancers (transdermal delivery) (examples include but arenot limited to monohydroxy or polyhydroxy alcohols, mono- or polyvalentalcohols, saturated or unsaturated fatty alcohols, saturated orunsaturated fatty esters, saturated or unsaturated dicarboxylic acids,essential oils, phosphatidyl derivatives, cephalin, terpenes, amides,ethers, ketones and ureas) plasticizers (examples include but are notlimited to diethyl phthalate and glycerol);

solvents (examples include but are not limited to ethanol, corn oil,cottonseed oil, glycerol, isopropanol, mineral oil, oleic acid, peanutoil, purified water, water for injection, sterile water for injectionand sterile water for irrigation);

stiffening agents (examples include but are not limited to cetylalcohol, cetyl esters wax, microcrystalline wax, paraffin, stearylalcohol, white wax and yellow wax);

suppository bases (examples include but are not limited to cocoa butterand polyethylene glycols (mixtures));

surfactants (examples include but are not limited to benzalkoniumchloride, nonoxynol 10, oxtoxynol 9, polysorbate 80, sodium laurylsulfate and sorbitan mono-palmitate);

suspending agents (examples include but are not limited to agar,bentonite, carbomers, carboxymethylcellulose sodium, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,kaolin, methylcellulose, tragacanth and veegum);

sweetening agents (examples include but are not limited to aspartame,dextrose, glycerol, mannitol, propylene glycol, saccharin sodium,sorbitol and sucrose);

tablet anti-adherents (examples include but are not limited to magnesiumstearate and talc);

tablet binders (examples include but are not limited to acacia, alginicacid, carboxymethylcellulose sodium, compressible sugar, ethylcellulose,gelatin, liquid glucose, methylcellulose, non-crosslinked polyvinylpyrrolidone, and pregelatinized starch);

tablet and capsule diluents (examples include but are not limited todibasic calcium phosphate, kaolin, lactose, mannitol, microcrystallinecellulose, powdered cellulose, precipitated calcium carbonate, sodiumcarbonate, sodium phosphate, sorbitol and starch);

tablet coating agents (examples include but are not limited to liquidglucose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetatephthalate and shellac);

tablet direct compression excipients (examples include but are notlimited to dibasic calcium phosphate);

tablet disintegrants (examples include but are not limited to alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose,polacrillin potassium, cross-linked polyvinylpyrrolidone, sodiumalginate, sodium starch glycollate and starch);

tablet glidants (examples include but are not limited to colloidalsilica, corn starch and talc);

tablet lubricants (examples include but are not limited to calciumstearate, magnesium stearate, mineral oil, stearic acid and zincstearate);

tablet/capsule opaquants (examples include but are not limited totitanium dioxide);

tablet polishing agents (examples include but are not limited to carnubawax and white wax);

thickening agents (examples include but are not limited to beeswax,cetyl alcohol and paraffin);

tonicity agents (examples include but are not limited to dextrose andsodium chloride);

viscosity increasing agents (examples include but are not limited toalginic acid, bentonite, carbomers, carboxymethylcellulose sodium,methylcellulose, polyvinyl pyrrolidone, sodium alginate and tragacanth);and

wetting agents (examples include but are not limited toheptadecaethylene oxycetanol, lecithins, sorbitol monooleate,polyoxyethylene sorbitol monooleate, and polyoxyethylene stearate).

Pharmaceutical compositions according to the present invention can beillustrated as follows:

Sterile IV Solution:

A 5 mg/mL solution of the desired compound of this invention can be madeusing sterile, injectable water, and the pH is adjusted if necessary.The solution is diluted for administration to 1-2 mg/mL with sterile 5%dextrose and is administered as an IV infusion over about 60 min.

Lyophilised Powder for IV Administration:

A sterile preparation can be prepared with (i) 100-1000 mg of thedesired compound of this invention as a lyophilised powder, (ii) 32-327mg/mL sodium citrate, and (iii) 300-3000 mg Dextran 40. The formulationis reconstituted with sterile, injectable saline or dextrose 5% to aconcentration of 10 to 20 mg/mL, which is further diluted with saline ordextrose 5% to 0.2-0.4 mg/mL, and is administered either IV bolus or byIV infusion over 15-60 min.

Intramuscular Suspension:

The following solution or suspension can be prepared, for intramuscularinjection:

50 mg/mL of the desired, water-insoluble compound of this invention

5 mg/mL sodium carboxymethylcellulose

4 mg/mL TWEEN 80

9 mg/mL sodium chloride

9 mg/mL benzyl alcohol

Hard Shell Capsules:

A large number of unit capsules are prepared by filling standardtwo-piece hard galantine capsules each with 100 mg of powdered activeingredient, 150 mg of lactose, 50 mg of cellulose and 6 mg of magnesiumstearate.

Soft Gelatin Capsules:

A mixture of active ingredient in a digestible oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into molten gelatin to form soft gelatincapsules containing 100 mg of the active ingredient. The capsules arewashed and dried. The active ingredient can be dissolved in a mixture ofpolyethylene glycol, glycerin and sorbitol to prepare a water misciblemedicine mix.

Tablets:

A large number of tablets are prepared by conventional procedures sothat the dosage unit is 100 mg of active ingredient, 0.2 mg. ofcolloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg ofmicrocrystalline cellulose, 11 mg of starch, and 98.8 mg of lactose.Appropriate aqueous and non-aqueous coatings may be applied to increasepalatability, improve elegance and stability or delay absorption.

Immediate Release Tablets/Capsules:

These are solid oral dosage forms made by conventional and novelprocesses. These units are taken orally without water for immediatedissolution and delivery of the medication. The active ingredient ismixed in a liquid containing ingredient such as sugar, gelatin, pectinand sweeteners. These liquids are solidified into solid tablets orcaplets by freeze drying and solid state extraction techniques. The drugcompounds may be compressed with viscoelastic and thermoelastic sugarsand polymers or effervescent components to produce porous matricesintended for immediate release, without the need of water.

Combination Therapies

The term “combination” in the present invention is used as known topersons skilled in the art and may be present as a fixed combination, anon-fixed combination or kit-of-parts.

A “fixed combination” in the present invention is used as known topersons skilled in the art and is defined as a combination wherein thesaid first active ingredient and the said second active ingredient arepresent together in one unit dosage or in a single entity. One exampleof a “fixed combination” is a pharmaceutical composition wherein thesaid first active ingredient and the said second active ingredient arepresent in admixture for simultaneous administration, such as in aformulation. Another example of a “fixed combination” is apharmaceutical combination wherein the said first active ingredient andthe said second active ingredient are present in one unit without beingin admixture.

A non-fixed combination or “kit-of-parts” in the present invention isused as known to persons skilled in the art and is defined as acombination wherein the said first active ingredient and the said secondactive ingredient are present in more than one unit. One example of anon-fixed combination or kit-of-parts is a combination wherein the saidfirst active ingredient and the said second active ingredient arepresent separately. The components of the non-fixed combination orkit-of-parts may be administered separately, sequentially,simultaneously, concurrently or chronologically staggered.

The compounds of this invention can be administered as the solepharmaceutical agent or in combination with one or more otherpharmaceutical agents where the combination causes no unacceptableadverse effects. The present invention relates also to suchcombinations. For example, the compounds of this invention can becombined with known chemotherapeutic agents or anti-cancer agents, e.g.anti-hyper-proliferative or other indication agents, and the like, aswell as with admixtures and combinations thereof. Other indicationagents include, but are not limited to, anti-angiogenic agents, mitoticinhibitors, alkylating agents, anti-metabolites, DNA-intercalatingantibiotics, growth factor inhibitors, cell cycle inhibitors, enzymeinhibitors, toposisomerase inhibitors, biological response modifiers, oranti-hormones.

The term “chemotherapeutic anti-cancer agents”, includes but is notlimited to 131I-chTNT, abarelix, abiraterone, aclarubicin, aldesleukin,alemtuzumab, alitretinoin, altretamine, aminoglutethimide, amrubicin,amsacrine, anastrozole, arglabin, arsenic trioxide, asparaginase,azacitidine, basiliximab, BAY 1000394, belotecan, bendamustine,bevacizumab, bexarotene, bicalutamide, bisantrene, bleomycin,bortezomib, buserelin, busulfan, cabazitaxel, calcium folinate, calciumlevofolinate, capecitabine, carboplatin, carmofur, carmustine,catumaxomab, celecoxib, celmoleukin, cetuximab, chlorambucil,chlormadinone, chlormethine, cisplatin, cladribine, clodronic acid,clofarabine, copanlisib, crisantaspase, cyclophosphamide, cyproterone,cytarabine, dacarbazine, dactinomycin, darbepoetin alfa, dasatinib,daunorubicin, decitabine, degarelix, denileukin diftitox, denosumab,deslorelin, dibrospidium chloride, docetaxel, doxifluridine,doxorubicin, doxorubicin+estrone, eculizumab, edrecolomab, elliptiniumacetate, eltrombopag, endostatin, enocitabine, epirubicin, epitiostanol,epoetin alfa, epoetin beta, eptaplatin, eribulin, erlotinib, estradiol,estramustine, etoposide, everolimus, exemestane, fadrozole, filgrastim,fludarabine, fluorouracil, flutamide, formestane, fotemustine,fulvestrant, gallium nitrate, ganirelix, gefitinib, gemcitabine,gemtuzumab, glutoxim, goserelin, histamine dihydrochloride, histrelin,hydroxycarbamide, I-125 seeds, ibandronic acid, ibritumomab tiuxetan,idarubicin, ifosfamide, imatinib, imiquimod, improsulfan, interferonalfa, interferon beta, interferon gamma, ipilimumab, irinotecan,ixabepilone, lanreotide, lapatinib, lenalidomide, lenograstim, lentinan,letrozole, leuprorelin, levamisole, lisuride, lobaplatin, lomustine,lonidamine, masoprocol, medroxyprogesterone, megestrol, melphalan,mepitiostane, mercaptopurine, methotrexate, methoxsalen, Methylaminolevulinate, methyltestosterone, mifamurtide, miltefosine,miriplatin, mitobronitol, mitoguazone, mitolactol, mitomycin, mitotane,mitoxantrone, nedaplatin, nelarabine, nilotinib, nilutamide,nimotuzumab, nimustine, nitracrine, ofatumumab, omeprazole, oprelvekin,oxaliplatin, p53 gene therapy, paclitaxel, palifermin, palladium-103seed, pamidronic acid, panitumumab, pazopanib, pegaspargase, PEG-epoetinbeta (methoxy PEG-epoetin beta), pegfilgrastim, peginterferon alfa-2b,pemetrexed, pentazocine, pentostatin, peplomycin, perfosfamide,picibanil, pirarubicin, plerixafor, plicamycin, poliglusam,polyestradiol phosphate, polysaccharide-K, porfimer sodium,pralatrexate, prednimustine, procarbazine, quinagolide, radium-223chloride, raloxifene, raltitrexed, ranimustine, razoxane, refametinib,regorafenib, risedronic acid, rituximab, romidepsin, romiplostim,sargramostim, sipuleucel-T, sizofiran, sobuzoxane, sodium glycididazole,sorafenib, streptozocin, sunitinib, talaporfin, tamibarotene, tamoxifen,tasonermin, teceleukin, tegafur, tegafur+gimeracil+oteracil, temoporfin,temozolomide, temsirolimus, teniposide, testosterone, tetrofosmin,thalidomide, thiotepa, thymalfasin, tioguanine, tocilizumab, topotecan,toremifene, tositumomab, trabectedin, trastuzumab, treosulfan,tretinoin, trilostane, triptorelin, trofosfamide, tryptophan, ubenimex,valrubicin, vandetanib, vapreotide, vemurafenib, vinblastine,vincristine, vindesine, vinflunine, vinorelbine, vorinostat, vorozole,yttrium-90 glass microspheres, zinostatin, zinostatin stimalamer,zoledronic acid, zorubicin.

The compounds of the invention may also be administered in combinationwith protein therapeutics. Such protein therapeutics suitable for thetreatment of cancer or other angiogenic disorders and for use with thecompositions of the invention include, but are not limited to, aninterferon (e.g., interferon .alpha., .beta., or .gamma.) supraagonisticmonoclonal antibodies, Tuebingen, TRP-1 protein vaccine, Colostrinin,anti-FAP antibody, YH-16, gemtuzumab, infliximab, cetuximab,trastuzumab, denileukin diftitox, rituximab, thymosin alpha 1,bevacizumab, mecasermin, mecasermin rinfabate, oprelvekin, natalizumab,rhMBL, MFE-CP1+ZD-2767-P, ABT-828, ErbB2-specific immunotoxin, SGN-35,MT-103, rinfabate, AS-1402, B43-genistein, L-19 basedradioimmunotherapeutics, AC-9301, NY-ESO-1 vaccine, IMC-1C11, CT-322,rhCC10, r(m)CRP, MORAb-009, aviscumine, MDX-1307, Her-2 vaccine,APC-8024, NGR-hTNF, rhH1.3, IGN-311, Endostatin, volociximab, PRO-1762,lexatumumab, SGN-40, pertuzumab, EMD-273063, L19-IL-2 fusion protein,PRX-321, CNTO-328, MDX-214, tigapotide, CAT-3888, labetuzumab,alpha-particle-emitting radioisotope-llinked lintuzumab, EM-1421,HyperAcute vaccine, tucotuzumab celmoleukin, galiximab, HPV-16-E7,Javelin—prostate cancer, Javelin—melanoma, NY-ESO-1 vaccine, EGFvaccine, CYT-004-MelQbG10, WT1 peptide, oregovomab, ofatumumab,zalutumumab, cintredekin besudotox, WX-G250, Albuferon, aflibercept,denosumab, vaccine, CTP-37, efungumab, or 131I-chTNT-1/B. Monoclonalantibodies useful as the protein therapeutic include, but are notlimited to, muromonab-CD3, abciximab, edrecolomab, daclizumab,gentuzumab, alemtuzumab, ibritumomab, cetuximab, bevicizumab,efalizumab, adalimumab, omalizumab, muromomab-CD3, rituximab,daclizumab, trastuzumab, palivizumab, basiliximab, and infliximab.

A compound of general formula (I) as defined herein can optionally beadministered in combination with one or more of the following: ARRY-162,ARRY-300, ARRY-704, AS-703026, AZD-5363, AZD-8055, BEZ-235, BGT-226,BKM-120, BYL-719, CAL-101, CC-223, CH-5132799, deforolimus, E-6201,enzastaurin, GDC-0032, GDC-0068, GDC-0623, GDC-0941, GDC-0973, GDC-0980,GSK-2110183, GSK-2126458, GSK-2141795, MK-2206, novolimus, OSI-027,perifosine, PF-04691502, PF-05212384, PX-866, rapamycin, RG-7167,RO-4987655, RO-5126766, selumetinib, TAK-733, trametinib, triciribine,UCN-01, WX-554, XL-147, XL-765, zotarolimus, ZSTK-474.

Generally, the use of cytotoxic and/or cytostatic agents in combinationwith a compound or composition of the present invention will serve to:

(1) yield better efficacy in reducing the growth of a tumor or eveneliminate the tumor as compared to administration of either agent alone,

(2) provide for the administration of lesser amounts of the administeredchemotherapeutic agents,

(3) provide for a chemotherapeutic treatment that is well tolerated inthe patient with fewer deleterious pharmacological complications thanobserved with single agent chemotherapies and certain other combinedtherapies,

(4) provide for treating a broader spectrum of different cancer types inmammals, especially humans,

(5) provide for a higher response rate among treated patients,

(6) provide for a longer survival time among treated patients comparedto standard chemotherapy treatments,

(7) provide a longer time for tumor progression, and/or

(8) yield efficacy and tolerability results at least as good as those ofthe agents used alone, compared to known instances where other canceragent combinations produce antagonistic effects.

Methods of Sensitizing Cells to Radiation

In a distinct embodiment of the present invention, a compound of thepresent invention may be used to sensitize a cell to radiation. That is,treatment of a cell with a compound of the present invention prior toradiation treatment of the cell renders the cell more susceptible to DNAdamage and cell death than the cell would be in the absence of anytreatment with a compound of the invention. In one aspect, the cell istreated with at least one compound of the invention.

Thus, the present invention also provides a method of killing a cell,wherein a cell is administered one or more compounds of the invention incombination with conventional radiation therapy.

The present invention also provides a method of rendering a cell moresusceptible to cell death, wherein the cell is treated with one or morecompounds of the invention prior to the treatment of the cell to causeor induce cell death. In one aspect, after the cell is treated with oneor more compounds of the invention, the cell is treated with at leastone compound, or at least one method, or a combination thereof, in orderto cause DNA damage for the purpose of inhibiting the function of thenormal cell or killing the cell.

In one embodiment, a cell is killed by treating the cell with at leastone DNA damaging agent. That is, after treating a cell with one or morecompounds of the invention to sensitize the cell to cell death, the cellis treated with at least one DNA damaging agent to kill the cell. DNAdamaging agents useful in the present invention include, but are notlimited to, chemotherapeutic agents (e.g., cisplatinum), ionizingradiation (X-rays, ultraviolet radiation), carcinogenic agents, andmutagenic agents.

In another embodiment, a cell is killed by treating the cell with atleast one method to cause or induce DNA damage. Such methods include,but are not limited to, activation of a cell signalling pathway thatresults in DNA damage when the pathway is activated, inhibiting of acell signalling pathway that results in DNA damage when the pathway isinhibited, and inducing a biochemical change in a cell, wherein thechange results in DNA damage. By way of a non-limiting example, a DNArepair pathway in a cell can be inhibited, thereby preventing the repairof DNA damage and resulting in an abnormal accumulation of DNA damage ina cell.

In one aspect of the invention, a compound of the invention isadministered to a cell prior to the radiation or other induction of DNAdamage in the cell. In another aspect of the invention, a compound ofthe invention is administered to a cell concomitantly with the radiationor other induction of DNA damage in the cell. In yet another aspect ofthe invention, a compound of the invention is administered to a cellimmediately after radiation or other induction of DNA damage in the cellhas begun.

In another aspect, the cell is in vitro. In another embodiment, the cellis in vivo.

As mentioned supra, the compounds of the present invention havesurprisingly been found to effectively inhibit the spindle assemblycheckpoint and may therefore be used for the treatment or prophylaxis ofdiseases of uncontrolled cell growth, proliferation and/or survival,inappropriate cellular immune responses, or inappropriate cellularinflammatory responses, or diseases which are accompanied withuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, particularly in which the uncontrolled cell growth,proliferation and/or survival, inappropriate cellular immune responses,or inappropriate cellular inflammatory responses are affected byinhibition of the spindle assembly checkpoint, such as, for example,haematological tumours, solid tumours, and/or metastases thereof, e.g.leukaemias and myelodysplastic syndrome, malignant lymphomas, head andneck tumours including brain tumours and brain metastases, tumours ofthe thorax including non-small cell and small cell lung tumours,gastrointestinal tumours, endocrine tumours, mammary and othergynaecological tumours, urological tumours including renal, bladder andprostate tumours, skin tumours, and sarcomas, and/or metastases thereof.

In accordance with another aspect therefore, the present inventioncovers a compound of general formula (I), or a stereoisomer, a tautomer,an N-oxide, a hydrate, a solvate, or a salt thereof, particularly apharmaceutically acceptable salt thereof, or a mixture of same, asdescribed and defined herein, for use in the treatment or prophylaxis ofa disease, as mentioned supra.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I), described supra, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, particularly a pharmaceutically acceptable salt thereof, or amixture of same, for the prophylaxis or treatment of a disease.

Another particular aspect of the present invention is therefore the useof a compound of general formula (I) described supra for manufacturing apharmaceutical composition for the treatment or prophylaxis of adisease.

The diseases referred to in the two preceding paragraphs are diseases ofuncontrolled cell growth, proliferation and/or survival, inappropriatecellular immune responses, or inappropriate cellular inflammatoryresponses, or diseases which are accompanied with uncontrolled cellgrowth, proliferation and/or survival, inappropriate cellular immuneresponses, or inappropriate cellular inflammatory responses, such as,for example, haematological tumours, solid tumours, and/or metastasesthereof, e.g. leukaemias and myelodysplastic syndrome, malignantlymphomas, head and neck tumours including brain tumours and brainmetastases, tumours of the thorax including non-small cell and smallcell lung tumours, gastrointestinal tumours, endocrine tumours, mammaryand other gynaecological tumours, urological tumours including renal,bladder and prostate tumours, skin tumours, and sarcomas, and/ormetastases thereof.

The term “inappropriate” within the context of the present invention, inparticular in the context of “inappropriate cellular immune responses,or inappropriate cellular inflammatory responses”, as used herein, is tobe understood as meaning a response which is less than, or greater thannormal, and which is associated with, responsible for, or results in,the pathology of said diseases.

Preferably, the use is in the treatment or prophylaxis of diseases,wherein the diseases are haemotological tumours, solid tumours and/ormetastases thereof.

Method of Treating Hyper-Proliferative Disorders

The present invention relates to a method for using the compounds of thepresent invention and compositions thereof, to treat mammalianhyper-proliferative disorders. Compounds can be utilized to inhibit,block, reduce, decrease, etc., cell proliferation and/or cell division,and/or produce apoptosis. This method comprises administering to amammal in need thereof, including a human, an amount of a compound ofthis invention, or a pharmaceutically acceptable salt, isomer,polymorph, metabolite, hydrate, solvate or ester thereof; etc. which iseffective to treat the disorder. Hyperproliferative disorders includebut are not limited, e.g., psoriasis, keloids, and other hyperplasiasaffecting the skin, benign prostate hyperplasia (BPH), solid tumours,such as cancers of the breast, respiratory tract, brain, reproductiveorgans, digestive tract, urinary tract, eye, liver, skin, head and neck,thyroid, parathyroid and their distant metastases. Those disorders alsoinclude lymphomas, sarcomas, and leukaemias.

Examples of breast cancer include, but are not limited to invasiveductal carcinoma, invasive lobular carcinoma, ductal carcinoma in situ,and lobular carcinoma in situ.

Examples of cancers of the respiratory tract include, but are notlimited to small-cell and non-small-cell lung carcinoma, as well asbronchial adenoma and pleuropulmonary blastoma.

Examples of brain cancers include, but are not limited to brain stem andhypothalamic glioma, cerebellar and cerebral astrocytoma,medulloblastoma, ependymoma, anaplastic astrocytoma, diffuseastrocytoma, glioblastoma, oligodendroglioma, secondary glioblastomamultiforme as well as neuroectodermal and pineal tumour.

Tumours of the male reproductive organs include, but are not limited toprostate and testicular cancer. Tumours of the female reproductiveorgans include, but are not limited to endometrial, cervical, ovarian,vaginal, and vulvar cancer, as well as sarcoma of the uterus.

Tumours of the digestive tract include, but are not limited to anal,colon, colorectal, oesophageal, gallbladder, gastric, pancreatic,rectal, small-intestine, and salivary gland cancers.

Tumours of the urinary tract include, but are not limited to bladder,penile, kidney, renal pelvis, ureter, urethral and human papillary renalcancers.

Eye cancers include, but are not limited to intraocular melanoma andretinoblastoma. Examples of liver cancers include, but are not limitedto hepatocellular carcinoma (liver cell carcinomas with or withoutfibrolamellar variant), cholangiocarcinoma (intrahepatic bile ductcarcinoma), and mixed hepatocellular cholangiocarcinoma.

Skin cancers include, but are not limited to squamous cell carcinoma,Kaposi's sarcoma, malignant melanoma, Merkel cell skin cancer, andnon-melanoma skin cancer.

Head-and-neck cancers include, but are not limited to laryngeal,hypopharyngeal, nasopharyngeal, oropharyngeal cancer, lip and oralcavity cancer and squamous cell. Lymphomas include, but are not limitedto AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-celllymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of thecentral nervous system.

Sarcomas include, but are not limited to sarcoma of the soft tissue,osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, andrhabdomyosarcoma.

Leukemias include, but are not limited to acute myeloid leukemia, acutelymphoblastic leukemia, chronic lymphocytic leukemia, chronicmyelogenous leukemia, and hairy cell leukemia.

These disorders have been well characterized in humans, but also existwith a similar etiology in other mammals, and can be treated byadministering pharmaceutical compositions of the present invention.

The term “treating” or “treatment” as stated throughout this document isused conventionally, e.g., the management or care of a subject for thepurpose of combating, alleviating, reducing, relieving, improving thecondition of, etc., of a disease or disorder, such as a carcinoma.

Methods of Treating Angiogenic Disorders

The present invention also provides methods of treating disorders anddiseases associated with excessive and/or abnormal angiogenesis.

Inappropriate and ectopic expression of angiogenesis can be deleteriousto an organism. A number of pathological conditions are associated withthe growth of extraneous blood vessels. These include, e.g., diabeticretinopathy, ischemic retinal-vein occlusion, and retinopathy ofprematurity [Aiello et al. New Engl. J. Med. 1994, 331, 1480; Peer etal. Lab. Invest. 1995, 72, 638], age-related macular degeneration [AMD;see, Lopez et al. Invest. Opththalmol. Vis. Sci. 1996, 37, 855],neovascular glaucoma, psoriasis, retrolental fibroplasias, angiofibroma,inflammation, rheumatoid arthritis (RA), restenosis, in-stentrestenosis, vascular graft restenosis, etc. In addition, the increasedblood supply associated with cancerous and neoplastic tissue, encouragesgrowth, leading to rapid tumour enlargement and metastasis. Moreover,the growth of new blood and lymph vessels in a tumour provides an escaperoute for renegade cells, encouraging metastasis and the consequencespread of the cancer. Thus, compounds of the present invention can beutilized to treat and/or prevent any of the aforementioned angiogenesisdisorders, e.g., by inhibiting and/or reducing blood vessel formation;by inhibiting, blocking, reducing, decreasing, etc. endothelial cellproliferation or other types involved in angiogenesis, as well ascausing cell death or apoptosis of such cell types.

Dose and Administration

Based upon standard laboratory techniques known to evaluate compoundsuseful for the treatment of hyper-proliferative disorders and angiogenicdisorders, by standard toxicity tests and by standard pharmacologicalassays for the determination of treatment of the conditions identifiedabove in mammals, and by comparison of these results with the results ofknown medicaments that are used to treat these conditions, the effectivedosage of the compounds of this invention can readily be determined fortreatment of each desired indication. The amount of the activeingredient to be administered in the treatment of one of theseconditions can vary widely according to such considerations as theparticular compound and dosage unit employed, the mode ofadministration, the period of treatment, the age and sex of the patienttreated, and the nature and extent of the condition treated.

The total amount of the active ingredient to be administered willgenerally range from about 0.001 mg/kg to about 200 mg/kg body weightper day, and preferably from about 0.01 mg/kg to about 20 mg/kg bodyweight per day. Clinically useful dosing schedules will range from oneto three times a day dosing to once every four weeks dosing. Inaddition, “drug holidays” in which a patient is not dosed with a drugfor a certain period of time, may be beneficial to the overall balancebetween pharmacological effect and tolerability. A unit dosage maycontain from about 0.5 mg to about 1500 mg of active ingredient, and canbe administered one or more times per day or less than once a day. Theaverage daily dosage for administration by injection, includingintravenous, intramuscular, subcutaneous and parenteral injections, anduse of infusion techniques will preferably be from 0.01 to 200 mg/kg oftotal body weight. The average daily rectal dosage regimen willpreferably be from 0.01 to 200 mg/kg of total body weight. The averagedaily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kgof total body weight. The average daily topical dosage regimen willpreferably be from 0.1 to 200 mg administered between one to four timesdaily. The transdermal concentration will preferably be that required tomaintain a daily dose of from 0.01 to 200 mg/kg. The average dailyinhalation dosage regimen will preferably be from 0.01 to 100 mg/kg oftotal body weight.

Of course the specific initial and continuing dosage regimen for eachpatient will vary according to the nature and severity of the conditionas determined by the attending diagnostician, the activity of thespecific compound employed, the age and general condition of thepatient, time of administration, route of administration, rate ofexcretion of the drug, drug combinations, and the like. The desired modeof treatment and number of doses of a compound of the present inventionor a pharmaceutically acceptable salt or ester or composition thereofcan be ascertained by those skilled in the art using conventionaltreatment tests.

Preferably, the diseases of said method are haematological tumours,solid tumour and/or metastases thereof.

The compounds of the present invention can be used in particular intherapy and prevention, i.e. prophylaxis, of tumour growth andmetastases, especially in solid tumours of all indications and stageswith or without pre-treatment of the tumour growth.

Methods of testing for a particular pharmacological or pharmaceuticalproperty are well known to persons skilled in the art.

The example testing experiments described herein serve to illustrate thepresent invention and the invention is not limited to the examplesgiven.

Biological Assays:

Examples were tested in selected biological assays one or more times.When tested more than once, data are reported as either average valuesor as median values, wherein

-   -   the average value, also referred to as the arithmetic mean        value, represents the sum of the values obtained divided by the        number of times tested, and    -   the median value represents the middle number of the group of        values when ranked in ascending or descending order. If the        number of values in the data set is odd, the median is the        middle value. If the number of values in the data set is even,        the median is the arithmetic mean of the two middle values.

Examples were synthesized one or more times. When synthesized more thanonce, data from biological assays represent average values or medianvalues calculated utilizing data sets obtained from testing of one ormore synthetic batch.

Mutant IDH1 R132H Biochemical Assay

mIDH1 catalyzes the NADPH-dependent reduction of alpha-ketoglutarate(α-KG) to (2R)-2-hydroxyglutarate (2-HG). NADPH consumption was measuredby luminescent readout.

The biochemical reactions were performed at 32° C. in 384-well platesusing a reaction volume of 41 μL and the following assay bufferconditions: 50 mM Tris pH 7.5, 100 mM NaCl, 20 mM MgCl₂, 0.05% BSA,0.01% Brij, 1 μM NADPH, and 250 μM α-KG. The IDH1 R132H enzyme was usedin a final concentration of 1.5 nM. Test compounds were used in aconcentration range between 0.002 and 10 μM. The final DMSOconcentration was 2.4%.

The reaction was incubated for 30 minutes, then 40 μL of detection mix(0.75 μg/ml Luciferase, 0.02 U/ml Oxidoreductase, 4 μg/mL FMN, 2 μL/mldecanal/ethanol, 50 mM Tris pH 7.5, 0.5% Glycerin, 0.01% Tween-20, 0.05%BSA) was added. Luminescence was measured on a luminescent reader (10seconds measuring time, 1 second integration period, 30% sensitivity).The decrease in luminescence is proportional to mIDH1 activity. IC₅₀values are determined by interpolation from plots of relativeluminescence versus inhibitor concentration.

TABLE 15 IC₅₀ values of selected examples in mutant IDH1 R132Hbiochemical assay Example Mutant IDH1 R132H IC₅₀ [μM] 2-8 0.41 2-9 0.022-110 0.46 2-111 0.04 2-111-1 0.08 2-111-2 0.38 2-112 >10 2-113 0.082-114 0.30 2-114-1 1.73 2-114-2 0.29 2-115 0.28 2-115-1 2.40 2-115-20.47 2-116 0.18 2-116-1 0.29 2-116-2 0.08 2-117 0.07 2-117-1 0.182-117-2 0.02 2-118 0.02 2-118-1 0.14 2-118-2 0.02 2-119 0.04 2-119-10.13 2-119-2 0.01 2-120 0.15 2-121 0.14 2-122 0.08 2-123 0.01 2-123-10.01 2-123-2 0.15 2-124 0.02 2-125 0.13 2-127 0.21 2-128 0.37 2-128-10.80 2-128-2 0.30 2-129 0.10 2-130 0.42 2-131 0.20 2-132 0.07 2-132-10.30 2-132-2 0.05 2-133 0.02 2-133-1 0.14 2-133-2 0.01 2-134 0.25 2-1350.11 2-135-1 0.60 2-135-2 0.04 2-138 >10 2-138-1 >10 2-138-2 3.7 2-1580.05 2-158-1 0.44 2-158-2 0.08 2-159 0.15 2-159-1 0.70 2-159-2 0.182-160 0.05 2-160-1 0.20 2-160-2 0.03 2-161 0.08 2-161-1 0.75 2-161-20.08 2-162 0.005 2-162-1 0.01 2-162-2 0.009 2-163 0.02 2-163-1 0.062-163-2 0.02 2-164 0.02 2-164-1 0.01 2-164-2 0.01 2-165 0.03 2-165-10.08 2-165-2 0.07 2-166 0.06 2-166-1 0.26 2-166-2 0.05 2-167 0.042-167-1 0.17 2-167-2 0.03 2-168 0.10 2-168-1 0.95 2-168-2 0.06 2-1690.01 2-169-1 0.02 2-169-2 0.01 2-170 0.008 2-170-1 0.02 2-170-2 0.0092-171 0.02 2-171-1 0.04 2-171-2 0.009 2-172 0.50 2-172-1 1.6 2-172-20.50 2-173 0.17 2-173-1 1.1 2-173-2 0.10 2-174 0.06 2-174-1 0.14 2-174-20.06 2-175 0.02 2-175-1 0.07 2-175-2 0.009 2-176 0.17 2-176-1 0.602-176-2 0.09 2-177 0.03 2-177-1 0.10 2-177-2 0.02 2-178 0.50 2-179 >102-180 >10 2-181 3.0 2-182 2.0 2-183 0.70 2-184 4.1 2-185 1.6 2-186 102-187 4.1 2-188 4.0 2-189 7.1 2-190 10 2-191 2.5 2-192 5.8 2-193 102-194 >10 2-195 0.10 2-196 0.09 2-197 0.03 2-198 0.07 2-198-1 0.482-198-2 0.03 2-199 0.23 2-199-1 0.62 2-199-2 0.17 2-200 0.20 2-200-10.42 2-200-2 0.08 2-201 0.18 2-202 0.06 2-203 0.02 2-204 0.05 2-205 0.072-205-1 0.38 2-205-2 0.05 2-206 0.03 2-206-1 0.13 2-206-2 0.05 2-2070.04 2-208 1.7 2-208-1 3.5 2-208-2 0.70 2-209 1.9 2-209-1 7.0 2-209-21.5 2-210 0.90 2-210-1 10 2-210-2 0.49 2-211 0.43 2-212 0.09 2-213 0.032-213-1 0.06 2-213-2 0.01 2-214 0.12 2-214-1 0.40 2-214-2 0.03 2-2150.04 2-215-1 0.18 2-215-2 0.02 2-216 0.25 2-217 0.50 2-218 0.60 2-2190.24 2-219-1 1.4 2-219-2 0.22 2-220 1.7 2-220-1 2.6 2-220-2 0.70 2-2210.85 2-221-1 1.9 2-221-2 0.73 2-222 0.02 2-223 0.04 2-224 0.03 2-2250.03 2-225-1 0.60 2-225-2 0.05 2-226 0.13 2-226-1 1.2 2-226-2 0.22 2-2270.04 2-228 0.08 2-229 0.03 2-230 0.06 2-230-1 0.58 2-230-2 0.03 2-2310.02 2-231-1 0.19 2-231-2 0.02 2-232 0.02 2-233 0.05 2-233-1 0.632-233-2 0.02 2-234 0.30 2-234-1 3.3 2-234-2 0.35 2-235 0.03 2-236 0.032-236-1 0.10 2-236-2 0.01 2-237 0.03 2-237-1 0.04 2-237-2 0.009 2-2380.12 2-238-1 0.25 2-238-2 0.06 2-239 0.02 2-240 0.02 2-241 0.04 2-2420.08

Mutant IDH1 Cellular Assay

Levels of (2R)-2-hydroxyglutarate (2HG) were measured in medium of acell line with overexpression of mutated isocitrate dehydrogenase (mIDH)protein. mIDH catalyzes the NADPH-dependent reduction ofalpha-ketoglutarate to 2-HG. Cells (LN229 R132H, Mohrenz et al.,Apoptosis (2013) 18:1416-1425) were grown in DMEM containing 10% FCS.They were harvested by trypsin and seeded into 96-well plates. Cellswere incubated overnight at 37° C. in 5% CO₂. The next day testcompounds were added to each cell well. The final concentration of DMSOwas 0.1% and DMSO controls were included. The plates were then placed inan incubator for 24 hours.

2-HG was measured according to Balss et al. (Acta Neuropathol (2012)124: 883-891). Briefly, HClO₄ was added to each well and the plates werecentrifuged. Aliquots are removed and incubated with hydroxyglutaratedehydrogenase (HGDH), diaphorase, NAD+, and resazurin. The conversion ofresazurin to resorufin was detected by fluorescence spectroscopy at Ex540 nm Em 600 nm. The increase in fluorescence is proportional to 2-HGproduction. IC₅₀ values are determined by interpolation from plots ofrelative fluorescence vs inhibitor concentration.

TABLE 16 IC₅₀ values of selected examples in mutant IDH1 cellular assayExample Mutant IDH1 IC₅₀ [μM] 2-9 0.32 2-111 0.06 2-111-1 0.15 2-111-20.50 2-113 0.22 2-114 0.30 2-114-2 0.21 2-115 0.20 2-116 0.62 2-117 0.352-118 0.17 2-118-1 0.80 2-118-2 0.08 2-119 0.07 2-120 3.5 2-121 1.02-122 3.0 2-123 0.6 2-123-1 0.3 2-124 3.0 2-125 >10 2-132-2 0.22 2-1330.12 2-135-2 0.17 2-138-2 6.0 2-158 0.04 2-158-1 0.21 2-158-2 0.12 2-1590.10 2-159-2 0.20 2-160 0.10 2-160-1 0.43 2-160-2 0.06 2-161 0.162-161-2 0.06 2-162-1 0.26 2-162-2 0.03 2-163 0.10 2-163-1 2.0 2-163-20.18 2-164 0.01 2-164-1 0.26 2-164-2 0.02 2-165 0.03 2-166 0.04 2-166-10.20 2-166-2 0.05 2-167 0.08 2-167-1 0.70 2-167-2 0.04 2-168 0.102-168-2 0.05 2-169 0.02 2-169-1 0.12 2-169-2 0.03 2-170 0.01 2-170-10.19 2-170-2 0.01 2-171 0.05 2-171-1 0.70 2-171-2 0.08 2-173 0.092-173-2 0.04 2-174 0.40 2-175 0.08 2-175-1 0.43 2-175-2 0.06 2-176 0.482-176-2 0.12 2-177 0.10 2-177-1 1.7 2-177-2 0.19 2-195 2.0 2-196 0.652-197 0.70 2-198 1.3 2-198-1 4.8 2-198-2 0.6 2-199 2.8 2-199-2 2.5 2-2002.1 2-200-2 3.8 2-201 0.08 2-202 0.70 2-203 0.40 2-204 1.3 2-205 0.702-206 1.0 2-206-1 1.9 2-206-2 0.13 2-207 0.80 2-207-1 0.95 2-207-2 0.122-212 0.05 2-213 0.06 2-214 0.43 2-215 0.12 2-215-1 0.68 2-215-2 0.152-216 1.3 2-219 1.8 2-222 0.18 2-223 1.2 2-224 0.65 2-225 0.18 2-225-20.30 2-226 0.48 2-226-2 0.95 2-227 0.48 2-228 0.18 2-229 0.19 2-230 0.852-230-2 0.32 2-231 0.18 2-231-1 0.42 2-231-2 0.05 2-232 0.03 2-233 0.402-233-2 0.11 2-234 0.85 2-235 0.30 2-236 0.50 2-236-1 1.7 2-237 0.182-237-1 0.38 2-237-2 0.05 2-238 1.5 2-238-1 2.1 2-238-2 0.23 2-239 0.162-240 0.09 2-241 0.32 2-242 1.8 2-243 2.2 2-244 0.12 2-245 0.38 2-2540.28 2-255 0.06

1-26. (canceled) 27: A method of treatment or prophylaxis of a diseasecomprising administering to a patient in need thereof a therapeuticallyeffect amount of a compound of formula (I):

wherein: R¹ is a halogen atom or a group selected from the groupconsisting of: C₁-C₆-alkyl, C₃-C₆-cycloalkyl, C₁-C₆-alkoxy,C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy,(C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, cyano, nitro, (C₁-C₆-alkyl)-S—,(C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—, (C₁-C₆-haloalkyl)-S—,(C₁-C₆-haloalkyl)-S(═O)—, (C₁-C₆-haloalkyl)-S(═O)₂—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, —N(R¹⁴)C(═O)R¹⁶, aryl-O—,aryl-(C₁-C₃-alkyl)-, heteroaryl-O—, and heteroaryl-(C₁-C₃-alkyl)-,wherein said aryl and heteroaryl groups are optionally substituted withone or two substituents, which are independently selected from the groupconsisting of: C₁-C₃-alkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano,—C(═O)OR¹³, and —C(═O)N(R¹⁴)R⁵; R² is a hydrogen atom; R³ is a hydrogenatom; R⁴ is a hydrogen atom or a halogen atom; R⁵ is a group selectedfrom the group consisting of: R¹³OC(═O)—(C₁-C₆-alkyl)-,R¹³OC(═O)—(C₂-C₆-alkenyl)-, R¹³OC(═O)—(C₁-C₆-alkoxy)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkyl)-, R¹⁴(R¹⁵)NC(═O)—(C₂-C₆-alkenyl)-, andR¹⁴(R¹⁵)NC(═O)—(C₁-C₆-alkoxy)-; R⁶ is a hydrogen atom, a halogen atom,or a group selected from the group consisting of: C₁-C₆-alkyl,C₁-C₆-alkoxy, (C₁-C₃-alkoxy)-(C₁-C₃-alkyl)-, C₃-C₆-cycloalkyl,C₃-C₆-cycloalkyloxy, C₁-C₆-haloalkyl, C₁-C₆-haloalkoxy, cyano, nitro,(C₁-C₆-alkyl)-S—, (C₁-C₆-alkyl)-S(═O)—, (C₁-C₆-alkyl)-S(═O)₂—,(C₁-C₆-haloalkyl)-S—, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶; R⁷ is a hydrogenatom; R⁸ is a C₁-C₃-alkyl group; R⁹, R¹⁰, and R¹¹ are independentlyselected from the group consisting of a hydrogen atom and C₁-C₃-alkyl;R¹² is a hydrogen atom; R¹³ is a hydrogen atom or a group selected fromthe group consisting of: C₁-C₆-alkyl, C₃-C₆-cycloalkyl,HO—(C₂-C₆-alkyl)-, and (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-; R¹⁴ and R¹⁵ areindependently selected from the group consisting of: a hydrogen atom,C₁-C₆-alkyl, C₃-C₆-cycloalkyl, HO—(C₂-C₆-alkyl)-,(C₁-C₃-alkoxy)-(C₂-C₆-alkyl)-, C₁-C₆-haloalkyl, H₂N—(C₂-C₆-alkyl)-,(C₁-C₃-alkyl)N(H)(C₂-C₆-alkyl)-, (C₁-C₃-alkyl)₂N(C₂-C₆-alkyl)-,R¹³OC(═O)—(C₁-C₆-alkyl)-, 4- to 6-membered heterocycloalkyl, aryl,heteroaryl, aryl-(C₁-C₆-alkyl)-, and heteroaryl-(C₁-C₆-alkyl)-, whereinsaid aryl and heteroaryl groups are optionally substituted with one ortwo substituents, which are independently selected from the groupconsisting of: C₁-C₃-alkyl, C₃-C₆-cycloalkyl, C₁-C₃-alkoxy,C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, halogen, cyano,—C(═O)OR¹³, and —C(═O)NH₂; or R¹⁴ and R¹⁵ are taken together with thenitrogen atom to which they are attached to form a 4-6-memberedheterocycloalkyl, wherein said 4-6-membered heterocycloalkyl isoptionally substituted with one substituent selected from the groupconsisting of: C₁-C₃-alkyl, C₁-C₃-haloalkyl, C₁-C₃-alkoxy,C₁-C₃-haloalkoxy, C₃-C₆-cycloalkyl, C₃-C₆-cycloalkyloxy, amino, hydroxy,halogen, and cyano; or wherein said 4-6-membered heterocycloalkyl isoptionally substituted with two halogen atoms; and R¹⁶ is a hydrogenatom or a group selected from the group consisting of: C₁-C₆-alkyl,HO—(C₁-C₆-alkyl)-, C₃-C₆-cycloalkyl, HO—(C₃-C₆-cycloalkyl)-,C₁-C₆-haloalkyl, (C₁-C₃-alkoxy)-(C₁-C₆-alkyl)-, aryl, heteroaryl, and 4-to 6-membered heterocycloalkyl, wherein said aryl and heteroaryl groupsare optionally substituted with one or two substituents, which areindependently selected from the group consisting of: C₁-C₃-alkyl,C₃-C₆-cycloalkyl, C₁-C₃-alkoxy, C₃-C₆-cycloalkyloxy, C₁-C₃-haloalkyl,C₁-C₃-haloalkoxy, halogen, cyano, —C(═O)OR¹³, and —C(═O)N(R¹⁴)R¹⁵, or astereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof, or a mixture of any of the foregoing. 28: The method of claim27, wherein: R¹ is a group selected from the group consisting of:C₁-C₃-alkyl, C₁-C₃-alkoxy, C₁-C₃-haloalkyl, C₁-C₃-haloalkoxy, cyano,nitro, (C₁-C₃-alkyl)-S(═O)₂—, (C₁-C₃-haloalkyl)-S—, —C(═O)OR¹³,—C(═O)N(R¹⁴)R¹⁵, —N(R¹⁴)R¹⁵, and —N(R¹⁴)C(═O)R¹⁶. 29: The method ofclaim 27, wherein: R¹ is a group selected from the group consisting of:—CF₃, —O—CF₃, —S—CF₃, —O—CH₂—CH₃, —O—C(H)(CH₃)₂, —CN, —C(H)(CH₃)₂, and—C(═O)OH. 30: The method of claim 27, wherein: R⁵ is a group selectedfrom the group consisting of: R¹³OC(═O)—(C₁-C₃-alkyl)-,R¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkyl)-, R¹³OC(═O)—(C₂-C₄-alkenyl)-,R¹⁴(R¹⁵)NC(═O)—(C₂-C₄-alkenyl)-, R¹³OC(═O)—(C₁-C₃-alkoxy)-, andR¹⁴(R¹⁵)NC(═O)—(C₁-C₃-alkoxy)-. 31: The method of claim 27, wherein: R⁵is a group selected from the group consisting of:R¹³OC(═O)—CH₂—CH₂—CH₂—, R¹³OC(═O)—CH₂—CH₂—, R¹³OC(═O)—CH₂—,R¹⁴(R¹⁵)NC(═O)—CH₂—CH₂—, R¹⁴(R¹⁵)NC(═O)—CH₂—, R¹³OC(═O)—CH₂—O—,R¹⁴(R¹⁵)NC(═O)—CH₂—O—,

P2 wherein * indicates the point of attachment of said groups to therest of the molecule. 32: The method of claim 27, wherein: R⁵ is a groupselected from the group consisting of: —O—CH₂—C(═O)—O—C(CH₃)₃,—O—CH₂—C(═O)—OH, —O—CH₂—CH₂—CH₂—C(═O)—OH, —O—CH₂—C(═O)—N(H)-cyclopropyl,—O—CH₂—C(═O)—N(H)—CH₂—C(═O)—O—CH₃, —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—O—CH₃,—O—CH₂—C(═O)—N(H)—CH₂—C(═O)—OH, —O—CH₂—C(═O)—N(CH₃)—CH₂—C(═O)—OH,—CH₂—CH₂—C(═O)—O—CH₃, —CH₂—CH₂—C(═O)—OH, —CH₂—C(═O)—O—CH₃,—CH₂—C(═O)—OH, —CH₂—CH₂—C(═O)—NH₂, —CH₂—CH₂—C(═O)—N(CH₃)₂,—C(H)═C(H)—C(═O)—OH, —C(H)═C(H)—C(═O)—O—CH₃, —C(H)═C(H)—C(═O)—NH₂, and—C(H)═C(H)—C(═O)—N(CH₃)₂. 33: The method of claim 27, wherein: R⁶ is ahydrogen atom, a fluorine atom, a —CH₃ group, a —O—CH₃ group or a—CH₂—O—CH₃ group. 34: The method of claim 27, wherein: R⁸ is a methylgroup; R⁹ is a hydrogen atom or a methyl group; R¹⁰ is a methyl group;and R¹¹ is a methyl group. 35: The method of claim 27, wherein: R¹³ is ahydrogen atom, a —CH₃ group or a —C(CH₃)₃ group. 36: The method of claim27, wherein: R¹⁴ is a hydrogen atom or a —CH₃ group. 37: The method ofclaim 27, wherein: R¹⁵ is a hydrogen atom or a group selected from thegroup consisting of: —CH₃, cyclopropyl, —CH₂—C(═O)—OH, —CH₂—C(═O)—O—CH₃,phenyl and pyridinyl, wherein said phenyl and pyridinyl groups areoptionally substituted with one or two substituents, which areindependently selected from the group consisting of: F, Cl, —CH₃, —CHF₂,—CF₃, —OCHF₂, —OCF₃, and —C(═O)OCH₃. 38: The method of claim 27, whereinthe compound of formula (I) is selected from the group consisting of:(±) methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate;(±)(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylicacid; (±) methyl(2E)-3-{2-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}acrylate;(±) methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±)(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide;(±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide;(±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)(2E)-N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide;(±)N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide;(±)({2-[(4-ethoxyphenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid; (±)[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid; (±)({2-[(4-isopropoxyphenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid; (±)({2-[(4-cyanophenyl)amino]-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid; (±) methylN-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate;(±)N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine;(±) methylN-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate;(±)N-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine;(±)4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid; (±)4-[(2-{[4-(isopropyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid; (±)4-[(2-{[4-(isopropoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid; (±)4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid; (±) methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate;(±) methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±)3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)3-(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)3-(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±) methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±)3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)3-(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±) methyl3-(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(±)3-(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±)3-(2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; (±) methyl3-{2-[(4-isopropoxyphenyl)amino]-6-methoxy-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoate;(±)3-{2-[(4-isopropoxyphenyl)amino]-6-methoxy-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoicacid; (±)4-({5-(2-carboxyethyl)-6-methoxy-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-yl}amino)benzoicacid; (±)2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}acetamide;(±)N-(2-chlorophenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-[(3-methylpyridin-2-yl)methyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-[(3-fluoropyridin-2-yl)methyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]-amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]-amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-[3-(trifluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-[4-(trifluoromethyl)phenyl]acetamide;(±)2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-[3-(trifluoromethyl)phenyl]acetamide;(±)N-[3-(difluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)methyl-3-({[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}amino)benzoate;(±)N-[2-chloro-5-(difluoromethyl)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino1}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-[4-(difluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-(2-methylphenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-(3-methylphenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±)N-[4-(trifluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;(±) methyl(2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl3-(1-[-3,3-dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(1-[-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;(±) methyl3-(1-[-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;(±) methyl(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-fluoro-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±) methyl(6-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;(±)(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)3-(1-[3,3-dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid; (±)(2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)3-(1-[3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid; (±)3-(1-[3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid; (±)(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-fluoro-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)(6-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (±)N,N-dimethyl-2-[(2-{[4-trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;and (±)N-cyclopropyl-N-methyl-2-[(2-{[4-trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide,or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, or asalt thereof, or a mixture of any of the foregoing. 39: The method ofclaim 27, wherein the compound of formula (I) is selected from the groupconsisting of: tert-butyl{[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]oxy}acetate;{[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]oxy}aceticacid; methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate;methyl(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate;(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylicacid;(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylicacid; methyl(2E)-3-{2-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}acrylate;methyl(2E)-3-{2-({4-[(trifluoromethyl)sulfanyl]phenyl}amino)-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}acrylate;methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethyl-cyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide;(2E)-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide;3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide;3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide;3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;(2E)-N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide;(2E)-N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylamide;N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide;N,N-dimethyl-3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanamide;({2-[(4-ethoxyphenyl)amino]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid;({2-[(4-ethoxyphenyl)amino]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid;[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid;[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]aceticacid;({2-[(4-isopropoxyphenyl)amino]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid;({2-[(4-isopropoxyphenyl)amino]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid;({2-[(4-cyanophenyl)amino]-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid;({2-[(4-cyanophenyl)amino]-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}oxy)aceticacid; methylN-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate;methylN-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate;N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-cyclopropyl-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine;N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine;methylN-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate;methylN-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycinate;N-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine;N-methyl-N-{[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}glycine;4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1 S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoic acid;4-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid;4-[(2-{[4-(isopropyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid;4-[(2-{[4-(isopropyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid;4-[(2-{[4-(isopropoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid;4-[(2-{[4-(isopropoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid;4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid;4-[(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]butanoicacid; methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate;methyl(2E)-3-(2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acrylate;methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; 3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoic acid;3-(6-methyl-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; 3-(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoic acid;3-(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; 3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoic acid;3-(6-methoxy-2-{[4-(trifluoromethyl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; methyl 3-(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate; methyl3-(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl3-(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;methyl 3-(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoate;3-(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid;3-(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; 3-(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoic acid;3-(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid; methyl3-{2-[(4-isopropoxyphenyl)amino]-6-methoxy-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoate;methyl3-{2-[(4-isopropoxyphenyl)amino]-6-methoxy-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoate;3-{2-[(4-isopropoxyphenyl)amino]-6-methoxy-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoic acid;3-{2-[(4-isopropoxyphenyl)amino]-6-methoxy-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl}propanoicacid; 4-({5-(2-carboxyethyl)-6-methoxy-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-yl}amino)benzoicacid;4-({5-(2-carboxyethyl)-6-methoxy-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-2-yl}amino)benzoicacid;2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}acetamide;2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-{[3-(trifluoromethyl)pyridin-2-yl]methyl}acetamide;N-(2-chlorophenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-(2-chlorophenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[(3-methylpyridin-2-yl)methyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[(3-methylpyridin-2-yl)methyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[(3-fluoropyridin-2-yl)methyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[(3-fluoropyridin-2-yl)methyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-{[3-chloro-5-(trifluoromethyl)pyridin-2-yl]methyl}-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[3-(trifluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[3-(trifluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1 S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-[4-(trifluoromethyl)phenyl]acetamide;2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-[4-(trifluoromethyl)phenyl]acetamide;2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-[3-(trifluoromethyl)phenyl]acetamide;2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]-N-[3-(trifluoromethyl)phenyl]acetamide;N-[3-(difluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[3-(difluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;methyl-3-({[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}amino)benzoate;methyl-3-({[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetyl}amino)benzoate;N-[2-chloro-5-(difluoromethyl)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[2-chloro-5-(difluoromethyl)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[4-(difluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[4-(difluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-(2-methylphenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-(2-methylphenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-(3-methylphenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-(3-methylphenyl)-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[4-(trifluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-[4-(trifluoromethoxy)phenyl]-2-[(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;methyl[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]acetate;methyl[2-{[4-(propan-2-yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl[2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl3-[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]propanoate;methyl[6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl[6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]acetate;methyl(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl3-(1-[(1S)-3,3-dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;methyl3-(1-[(1R)-3,3-dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;methyl3-(1-[(1S)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;methyl3-(1-[(1R)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;methyl3-(1-[(1S)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;methyl3-(1-[(1R)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H-benzimidazol-5-yl)propanoate;methyl3-[2-{[4-(propan-2-yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]propanoate;methyl3-[2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]propanoate;methyl(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl[6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl[6-fluoro-2-{[4-(propan-2-yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl[6-fluoro-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]acetate;methyl(6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-fluoro-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-fluoro-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl(6-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetate;methyl[6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl[6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]acetate;methyl[6-methoxy-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]acetate;(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetic acid;(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]aceticacid;[2-{[4-(propan-2-yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]aceticacid;[2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]aceticacid;3-(1-[(1S)-3,3-dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid;3-(1-[(1R)-3,3-dimethylcyclohexyl]-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid;(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;3-[2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]propanoicacid;3-(1-[(1S)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid;3-(1-[(1R)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yl)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid;3-(1-[(1S)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid;3-(1-[(1R)-3,3-dimethylcyclohexyl]-2-{[4-(propan-2-yloxy)phenyl]amino}-1H-benzimidazol-5-yl)propanoicacid;3-[1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]propanoicacid;(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methyl-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetic acid;(6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;[6-methyl-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]aceticacid;[6-methyl-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]aceticacid;[6-methyl-2-{[4-(propan-2-yloxy)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]aceticacid;[6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]aceticacid;[6-fluoro-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]aceticacid;6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl]aceticacid;[6-methoxy-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]aceticacid;(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methoxy-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methoxy-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methoxy-2-[4-(propan-2-yl)phenyl]amino-1-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-methoxy-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-fluoro-2-{[4-(propan-2-yl)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-fluoro-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid;(6-fluoro-2-{[4-(propan-2-yloxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; (6-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)acetic acid;(6-fluoro-2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)aceticacid; methyl3-[4-fluoro-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]propanoate;methyl3-{4-fluoro-2-[(4-isopropoxyphenyl)amino]-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl}propanoate;3-[4-fluoro-1-(3,3,5,5-tetramethylcyclohexyl)-2-{[4-(trifluoromethoxy)phenyl]amino}-1H-benzimidazol-5-yl]propanoicacid;3-{4-fluoro-2-[(4-isopropoxyphenyl)amino]-1-(3,3,5,5-tetramethylcyclohexyl)-1H-benzimidazol-5-yl}propanoicacid;N,N-dimethyl-2-[(2-{[4-trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N,N-dimethyl-2-[(2-{[4-trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;N-cyclopropyl-N-methyl-2-[(2-{[4-trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide;andN-cyclopropyl-N-methyl-2-[(2-{[4-trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)oxy]acetamide,or a tautomer, an N-oxide, a hydrate, a solvate, or a salt thereof, or amixture of any of the foregoing. 40: The method of claim 27, wherein thecompound of formula (I) is (±)3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(cis)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate,or a salt thereof. 41: The method of claim 27, wherein the compound offormula (I) is3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1R,5R)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, or a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof. 42: The method of claim 27, wherein the compound of formula (I)is is3-(2-{[4-(trifluoromethoxy)phenyl]amino}-1-[(1S,5S)-3,3,5-trimethylcyclohexyl]-1H-benzimidazol-5-yl)propanoicacid, or a tautomer, an N-oxide, a hydrate, a solvate, or a saltthereof. 43: The method of claim 27, wherein the disease is a disease ofuncontrolled cell growth, proliferation and/or survival, aninappropriate cellular immune response, or an inappropriate cellularinflammatory response. 44: The method of claim 43, wherein the diseaseof uncontrolled cell growth, proliferation and/or survival, aninappropriate cellular immune response, or an inappropriate cellularinflammatory response is a haematological tumour, a solid tumour and/ormetastases thereof. 45: The method of claim 44, wherein thehaematological tumour, solid tumour and/or metastases thereof isselected from the group consisting of leukaemias, myelodysplasticsyndrome, malignant lymphomas, head and neck tumours, brain tumours andbrain metastases, tumours of the thorax, non-small cell and small celllung tumours, gastrointestinal tumours, endocrine tumours, mammary andother gynaecological tumours, urological tumours, renal, bladdertumours, prostate tumours, skin tumours, and sarcomas, and/or metastasesthereof. 46: The method of claim 27, wherein the disease is responsiveto inhibition of mIDH1 activity.